Pyrazolopyrimidines, a process for their preparation and their use as medicine

ABSTRACT

Substituted pyrazolopyrimidine derivatives of formula (I)  
                 
wherein 
 
R 1  represents chloro or bromo; 
 
R 2 , R 3 , R 4 , R 5 , R 6  and R 7  independently represent e.g. hydrogen or C 1-6 -alkyl; 
 
R 8  represents a radical R 9  or a radical R 10 , whereby one of the two radicals R 8  represents R 9  and the other radical R 8  represents Ret; R 9  represents e.g. a phenyl or thiophene group, and R 10  represents e.g. hydrogen or methyl; 
are potent mGluR5 modulators and are useful for the prevention of acute and chronic neurological disorders.

FIELD OF THE INVENTION

The present invention relates to pyrazolopyrimidine derivatives, whichcan act as novel metabotropic glutamate receptor (mGluR) modulators,methods for their synthesis and their use as a medicament for thetreatment of various diseases and/or prevention of disorders, e.g.neurological disorders, by administration of such substances.

BACKGROUND OF THE INVENTION

Neuronal stimuli are transmitted by the central nervous system (CNS)through the interaction of a neurotransmitter released by a neuron,which neurotransmitter has a specific effect on a neuroreceptor ofanother neuron. L-glutamic acid is considered to be a major excitatoryneurotransmitter in the mammalian CNS, consequently playing a criticalrole in a large number of physiological processes. Glutamate-dependentstimulus receptors are divided into two main groups. The first groupcomprises ligand-controlled ion channels whereas the other comprisesmetabotropic glutamate receptors (mGluR). Metabotropic glutamatereceptors are a subfamily of G-protein-coupled receptors (GPCR). Thereis increasing evidence for a peripheral role of both ionotropic andmetabotropic glutamate receptors outside the CNS e.g., in chronic painstates.

At present, eight different members of these mGluRs are known. On thebasis of structural parameters such as sequence homology, the secondmessenger system utilized by these receptors and their differentaffinity to low-molecular weight compounds, these eight receptors can bedivided into three groups. MGluR1 and mGluR5 belong to Group I which arepositively coupled to phospholipase C and their activation leads to amobilization of intracellular calcium ions. MGluR2 and mGluR3 belong toGroup II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group III, bothof which are negatively coupled to adenylyl cyclase, i.e., theiractivation causes a reduction in second messenger cAMP and thus adampening of neuronal activity.

The mGluR5 modulators have been shown to modulate the effects of thepresynaptically released neurotransmitter glutamate via postsynapticmechanisms. Moreover, as these modulators can be both positive and/ornegative mGluR5 modulators, such modulators may increase or inhibit theeffects mediated through these metabotropic glutamate receptors.

Of particular interest are those modulators which are negative mGluR5modulators. Such modulators decrease the effects mediated throughmetabotropic glutamate receptors. Since a variety of patho-physiologicalprocesses and disease states affecting the CNS are thought to be relatedto abnormal glutamate neurotransmission, and mGluR5 receptors are shownto be expressed in several areas of the CNS, modulators of thesereceptors could be therapeutically beneficial in the treatment of CNSdiseases.

Therefore, mGluR5 positive or negative modulators may be administered toprovide neuroprotection and/or disease modification in the followingacute or chronic pathological conditions or to provide asymptomatological effect on the following conditions:

Alzheimer's disease, Creutzfeld-Jakob's syndrome/disease, bovinespongiform encephalopathy (BSE), prion related infections, diseasesinvolving mitochondrial dysfunction, diseases involving β-amyloid and/ortauopathy, Down's syndrome, hepatic encephalopathy, Huntington'sdisease, motor neuron diseases, amyotrophic lateral sclerosis (ALS),olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD),systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome,Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias,Parkinson's disease, Parkinson's dementia, mild cognitive impairment,cognitive deficits in various forms of mild cognitive impairment,cognitive deficits in various forms of dementia, dementia pugilistica,vascular and frontal lobe dementia, cognitive impairment, learningimpairment, eye injuries, eye diseases, eye disorders, glaucoma,retinopathy, macular degeneration, head or brain or spinal cordinjuries, head or brain or spinal cord trauma, trauma, hypoglycaemia,hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiacarrest or stroke or bypass operations or transplants, convulsions,epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonicepilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus,sound- or drug-induced inner ear insult, sound- or drug-inducedtinnitus, L-dopa-induced dykinesias, L-dopa-induced dykinesias inParkinson's disease therapy, dyskinesias, dyskinesia in Huntington'sdisease, drug induced dyskinesias, neuroleptic-induced dyskinesias,haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias,chorea, Huntington's chorea, athetosis; dystonia, stereotypy, ballism,tardive dyskinesias, tic disorder, torticollis spasmodicus,blepharospasm, focal and generalized dystonia, nystagmus, hereditarycerebellar ataxias, corticobasal degeneration, tremor, essential tremor,abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction,alcohol abuse, opiate addiction, opiate abuse, cocaine addiction,cocaine abuse, amphetamine addiction, amphetamine abuse, anxietydisorders, panic disorders, anxiety and panic disorders, social anxietydisorder (SAD), attention deficit hyperactivity disorder (ADHD),attention deficit syndrome (ADS), restless leg syndrome (RLS),hyperactivity in children, autism, dementia, dementia in Alzheimer'sdisease, dementia in Korsakoff syndrome, Korsakoff syndrome, vasculardementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDSencephalopathy, AIDS dementia complex, AIDS-related dementia, majordepressive disorder, major depression, depression, depression resultingfrom Borna virus infection, major depression resulting from Borna virusinfection, bipolar manic-depressive disorder, drug tolerance, drugtolerance to opioids, movement disorders, fragile-X syndrome, irritablebowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms,pain, chronic pain, acute pain, inflammatory pain, neuropathic pain,diabetic neuropathic pain (DNP), pain related to rheumatic arthritis,allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumaticstress disorder (PTSD), schizophrenia, positive or cognitive or negativesymptoms of schizophrenia, spasticity, Tourette's syndrome, urinaryincontinence, vomiting, pruritic conditions, pruritis, sleep disorders,micturition disorders, neuromuscular disorder in the lower urinarytract, gastroesophageal reflux disease (GERD), gastrointestinaldysfunction, lower esophageal sphincter (LES) disease, functionalgastrointestinal disorders, dyspepsia, regurgitation, respiratory tractinfection, bulimia nervosa, chronic laryngitis, asthma, reflux-relatedasthma, lung disease, eating disorders, obesity, obesity-relateddisorders, obesity abuse, food addiction, binge eating disorders,agoraphobia, generalized anxiety disorder, obsessive-compulsivedisorder, panic disorder, posttraumatic stress disorder, social phobia,phobic disorders, substance-induced anxiety disorder, delusionaldisorder, schizoaffective disorder, schizophreniform disorder,substance-induced psychotic disorder, or delirium.

The mGluR5 negative or positive modulators may also be administered toprovide inhibition of tumour cell growth, migration, invasion, adhesionand toxicity in the peripheral tissues, peripheral nervous system andCNS. MGluR5 modulators may be administered to provide therapeuticintervention in neoplasia, hyperplasia, dysplasia, cancer, carcinoma,sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cellcarcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer,prostate cancer, gastric cancer, liver cancer, colon cancer, colorectalcarcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve tissue,glioma, malignant glioma, astroglioma, neuroglioma, neuroblastoma,glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignantmelanoma, epithelial neoplasm, lymphoma, myeloma, Hodgkin's disease,Burkitt's lymphoma, leukemia, thymoma, and other tumours.

Further indications for mGluR5 negative or positive modulators includethose indications wherein a particular condition does not necessarilyexist but wherein a particular physiological parameter may be improvedthrough administration of the instant compounds, for example cognitiveenhancement, learning impairment and/or neuroprotection.

Positive modulators may be particularly useful in the treatment ofpositive and negative symptoms in schizophrenia and cognitive deficitsin various forms of dementia and mild cognitive impairment.

In the literature, several types of modulators of mGluR5 have alreadybeen described.

Furthermore, several types of pyrazolopyrimidine compounds have beendisclosed in the prior art.

Various methods for preparing substituted pyrazolopyrimidine derivativesare known, e.g. from G. Hajos and Z. Riedl, Science of Synthesis 109,613-678 (2002) and from Laura Bettinetti (Ph. D. Thesis, University ofErlangen, Germany, 2004).

In WO 2004/087153 various pyrazolopyrimidines of formula (XXII) aredescribed, which can act as small molecule immune potentiators (SMIP)and which can be used e.g. for cancer treatment.

Furthermore, in WO 2004/089471, the use of substitutedpyrazolo[1,5-a]pyrimidines or prodrugs or salts thereof are describedfor the preparation of a pharmaceutical composition for the treatment ofdisorders and diseases where it is desirable to modulate the activity ofthe enzyme 11βHSD1 or to inhibit 11βHSD1. In the document WO2004/089471, pyrazolo(1,5-a)pyrimidine derivates of the followinggeneral formula (C) are disclosed:

In WO 2003/037900, further specific pyrazolopyrimidine compounds aredescribed as inhibitors of ion-channels in human cells. In this documentcompounds having the following general formula (X) are described:

-   -   wherein    -   R¹ is e.g. alkyl; R² is a e.g. hydrogen or alkyl; or    -   R¹ and R² taken together with the nitrogen atom to which they        are optionally joined to form a 4- to 8-membered heterocycloaryl        ring;    -   R³ is e.g. hydrogen, alkyl, halo, amino or aryl;    -   R⁴ is e.g. hydrogen, halo, alkyl or aryl; and    -   R⁵ is a member selected from substituted or unsubstituted alkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl and substituted or unsubstituted heterocycloalkyl; R⁶        is e.g. hydrogen, halo or aryl; and    -   X is a member selected from O and S.

Several pyrazolopyrimidine compounds according to the present invention,however have been tested which are found to be not significantly activeas inhibitors of ion-channels in human cells. In this document WO2003/037900, compounds of the following two structures are mentioned asexample compounds (B308) and (B310), which however have shown noparticular activity as metabotropic glutamate receptor (mGluR5)modulators:

(6-Bromopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone

(6-Bromopyrazolo[1,5-a]pyrimidin-2-yl)-morpholin-4-yl-methanone

In WO 2003/101993 several types of pyrazolopyrimidine compounds andtheir use for the treatment of hepatitis infections are disclosed. WO2003/101993 deals with compounds of the following general formula (Z)

-   -   wherein:    -   G¹ is selected e.g. from the group of —OH, cyano, —C(O)—OH,        —C(O)—NR²R³, where R² and R³ taken together from a 5- or        6-membered heteroaromatic or saturated or partially unsaturated        heterocyclic ring, or    -   G² is independently are selected from the group consisting e.g.        of alkyl, cycloalkyl, aryl, heteroaryl, saturated or partially        unsaturated heterocyclic radical, trifluoromethyl,    -   G³ can be absent or is independently selected from the group        consisting of e.g. alkyl, cycloalkyl, aryl, heteroaryl,        saturated or partially unsaturated heterocyclic radical,    -   G² and G³, collectively, are attached at any two of positions        C7, C8 and C9 of the pyrimidine ring, the remaining position        being optionally substituted with alkyl, alkenyl, alkynyl, halo,        fluoroalkyl, hydroxyl, alkoxy, or cyano;    -   wherein the ring portion of any of said cycloalkyl, aryl,        aralkyl, heteroaryl, heteroarylalkyl, or heterocyclic radical in        G¹, G² or G³ can be optionally substituted.

In the document WO 2003/091256 particular pyrazolopyrimidine derivativeswhich have a NADPH-oxidase inhibitor activity are described. Thecompounds have the following general formula (Y)

-   -   wherein R_(1a), R_(2a), R₃-R₅ represent hydrogen, halogen, lower        alkyl that may be substituted, lower alkenyl that may be        substituted, lower alkynyl that may be substituted, cycloalkyl        that may be substituted, cycloalkenyl that may be substituted,        cycloalkynyl that may be substituted, aryl that may be        substituted, heterocyclic group that may be substituted,        hydroxyl, alkoxy that may be substituted, aryloxy that may be        substituted, heterocyclic oxy that may be substituted, acyl that        may be substituted, monosubstituted carbonyloxy that may be        substituted, carbamoyl that may be substituted, diazo, amidino        that may be substituted, azido, nitroso, nitro, amino that may        be substituted, imino that may be substituted, cyano, mercapto,        monosubstituted sulfinyl that may be substituted,        monosubstituted sulfonyl that may be substituted, sulfo, or        trisubstituted silyl, and any combinations of R_(1a), R_(2a),        R₃-R₅ may together form a ring structure.

A further pyrazolopyrimidine compound which has already been describedin the literature (see ChemBridge Corporation; Registry Nr. 833441-66-0;of Feb. 18, 2005), has the following structure (M):

(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,2,3,4-tetrahydro-isoquinolin-2-yl)-methanon

This compound, however has only a limited activity as metabotropicglutamate receptor (mGluR5) modulator and furthermore is not selective.

In WO 2006/015737 further heterocyclic compounds which can contain acarboxylic acid amid function are disclosed which have an activity atdopamine receptors and which can be used for the treatment ofCNS-diseases. As one example structure, pyrazolopyrimidines arementioned.

In WO 2002/088088 the synthesis of tetrahydro-isoquinolin compounds isdisclosed which can serve as intermediates for the synthesis ofpharmaceutically active compounds.

THE PRESENT INVENTION

It now has been found that certain pyrazolopyrimidine derivatives whichdiffer in structure from the known pyrazolopyrimidines, are potentmGluR5 modulators. Therefore, these substances may be therapeuticallybeneficial in the treatment of conditions which involve abnormalglutamate neurotransmission or in which modulation of mGluR5 receptorsresults in therapeutic benefit. These substances are preferablyadministered in the form of a pharmaceutical composition, wherein theyare present together with one or more pharmaceutically acceptablediluents, carriers, or excipients.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novel pharmaceuticalcompounds which are mGluR5 modulators and pharmaceutical compositionsthereof. It is a further object of the invention to provide a novelmethod of treating, eliminating, alleviating, palliating, orameliorating undesirable CNS disorders which involve abnormal glutamateneurotransmission by employing a compound of the invention or apharmaceutical composition containing the same.

An additional object of the invention is the provision of processes forproducing the pyrazolopyrimidine derivatives.

SUMMARY OF THE INVENTION

The invention in general deals with: A compound selected from those offormula (Ig)

-   -   wherein    -   R¹ represents chloro or bromo;    -   R², R³, R⁴, R⁵, R⁶ and R⁷, which may be the same or different,        each independently represent hydrogen, C₁₋₆alkyl, amino,        hydroxy, halogen, or trifluoromethyl;    -   R⁸ represents hydrogen, or C₁₋₆alkyl;    -   R⁹ represents aryl or heteroaryl, wherein the aryl or heteroaryl        group may be optionally substituted by one or more substituents        (e.g., 1, 2, or 3), which may be the same or different, selected        independently from halogen, amino, hydroxy, nitro, cyano,        trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy,        C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonyloxy, C₁₋₆alkylamino,        di-C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, C₁₋₆alkylenedioxy,        aryl, heteroaryl, heterocyclyl, and cycloC₃₋₁₂alkyl;    -   or R⁸ and R⁹ together with the carbon atoms to which they are        attached may form an unsaturated cyclic ring system containing 5        to 7 (i.e. 5, 6 or 7) carbon atoms, wherein 0 to 4 (i.e. 0, 1,        2, 3 or 4) of the carbon atoms of the ring system formed by R⁸        and R⁹ may be replaced by heteroatoms independently selected        from nitrogen, oxygen and sulfur and wherein the ring system may        be optionally substituted by one or more (e.g., 1, 2, or 3)        substituents, which may be the same or different, independently        selected from halogen, amino, hydroxy, nitro, cyano,        trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy,        C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonyloxy, C₁₋₆alkylamino,        di-C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, C₁₋₆alkylenedioxy,        aryl, heteroaryl, heterocyclyl, and cycloC₃₋₁₂alkyl;    -   and optical isomers, pharmaceutically acceptable salts,        hydrates, solvates, and polymorphs thereof; it being understood        that: the compound of Formula Ig does not represent:        (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone.

Furthermore, a compound of Formula (Ig), wherein

-   -   R⁸ represents hydrogen or methyl;    -   R¹ represents chloro or bromo;    -   R², R³, R⁴, R⁵, R⁶ and R⁷, which may be the same or different,        each independently represent hydrogen, C₁₋₆alkyl, amino,        hydroxy, halogen, or trifluoromethyl;    -   R⁹ represents aryl or heteroaryl, wherein the aryl or heteroaryl        group may be optionally substituted by one or more substituents        (e.g., 1, 2, or 3), which may be the same or different, selected        independently from halogen, amino, hydroxy, nitro, cyano,        trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy,        C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonyloxy, C₁₋₆alkylamino,        di-C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, C₁₋₆alkylenedioxy,        aryl, heteroaryl, heterocyclyl, and cycloC₃₋₁₂alkyl;    -   or R⁸ and R⁹ together with the carbon atoms to which they are        attached may form an unsaturated cyclic ring system containing 5        to 7 (i.e. 5, 6 or 7) carbon atoms, wherein 0 to 4 (i.e. 0, 1,        2, 3 or 4) of the carbon atoms of the ring system formed by R⁸        and R⁹ may be replaced by heteroatoms independently selected        from nitrogen, oxygen and sulfur and wherein the ring system may        be optionally substituted by one or more (e.g., 1, 2, or 3)        substituents, which may be the same or different, independently        selected from halogen, amino, hydroxy, nitro, cyano,        trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy,        C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonyloxy, C₁₋₆alkylamino,        di-C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, C₁₋₆alkylenedioxy,        aryl, heteroaryl, heterocyclyl, and cycloC₃₋₁₂alkyl.

Such a compound of Formula (Ig), wherein

-   -   R⁹ represents phenyl or monocyclic heteroaryl, wherein the        heteroaryl ring contains from 1 to 4 (i.e. 1, 2, 3 or 4)        heteroatoms selected independently from oxygen, sulfur and        nitrogen and wherein the phenyl or heteroaryl ring may be        optionally substituted by one to three substituents, which may        be the same or different, selected independently from halogen,        amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy,        aminocarbonyl, N—C₁₋₆alkylaminocarbonyl,        di-N,N—C₁₋₆alkylaminocarbonyl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₂₋₆alkenyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl,        C₁₋₆alkylcarbonyloxy, C₁₋₆alkylamino, di-C₁₋₆alkylamino,        C₁₋₆alkylcarbonylamino, C₁₋₆alkylenedioxy, aryl, heteroaryl,        heterocyclyl, and cycloC₃₋₁₂alkyl;    -   R¹ represents chloro or bromo;    -   R², R³, R⁴, R⁵, R⁶ and R⁷, which may be the same or different,        each independently represent hydrogen, C₁₋₆alkyl, amino,        hydroxy, halogen, or trifluoromethyl; and    -   R⁸ represents hydrogen, or methyl.

Such a compound of Formula (Ig), wherein

-   -   R⁸ represents hydrogen;    -   R⁹ represents phenyl, optionally substituted by one to two        substituents, which may be the same or different, selected        independently from halogen, amino, hydroxy, nitro, cyano,        trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy, and        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo; and    -   R², R³, R⁴, R⁵, R⁶ and R⁷, which may be the same or different,        each independently represent hydrogen, C₁₋₆alkyl, amino,        hydroxy, halogen, or trifluoromethyl.

Such a compound of Formula (Ig), wherein

-   -   R⁸ represents hydrogen;    -   R⁹ represents phenyl, optionally substituted by one to two        substituents, which may be the same or different, selected        independently from halogen, amino, hydroxy, nitro, cyano,        trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy, and        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo;    -   R², R³, R⁴ and R⁵, which may be the same or different, each        independently represent hydrogen or methyl; and    -   R⁶ and R⁷ represent hydrogen.

Such a compound of Formula (Ig), wherein

-   -   R⁸ represents hydrogen;    -   R⁹ represents phenyl, optionally substituted by one to two        substituents, which may be the same or different, selected        independently from halogen, amino, hydroxy, nitro, cyano,        trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy, and        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo;    -   R⁶ and R⁷ represent hydrogen; and    -   one of R², R³, R⁴ and R⁵ represents methyl and the remaining of        R², R³, R⁴ and R⁵ represent hydrogen.

Such a compound of Formula (Ig), wherein

-   -   R⁸ and R⁹ together with the carbon atoms to which they are        attached form an unsaturated cyclic ring system containing 6        carbon atoms, wherein 0 to 2 (i.e. 0, 1 or 2) of the carbon        atoms of the ring system formed by R⁸ and R⁹, may be replaced by        a heteroatom independently selected from nitrogen, oxygen and        sulfur and wherein the ring system may be optionally substituted        by one or more (e.g., 1, 2, or 3) substituents, which may be the        same or different, independently selected from halogen, amino,        hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy,        aminocarbonyl, N—C₁₋₆alkylaminocarbonyl,        di-N,N—C₁₋₆alkylaminocarbonyl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₂₋₆alkenyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl,        C₁₋₆alkylcarbonyloxy, C₁₋₆alkylamino, di-C₁₋₆alkylamino,        C₁₋₆alkylcarbonylamino, C₁₋₆alkylenedioxy, aryl, heteroaryl,        heterocyclyl, and cycloC₃₋₁₂alkyl;    -   R¹ represents chloro or bromo; and    -   R², R³, R⁴, R⁵, R⁶ and R⁷, which may be the same or different,        each independently represent hydrogen, C₁₋₆alkyl, amino,        hydroxy, halogen, or trifluoromethyl.

Such compound of Formula (Ig), wherein

-   -   R⁸ and R⁹ together with the carbon atoms to which they are        attached form a benzene ring system optionally substituted by        one to two substituents, which may be the same or different,        independently selected from halogen, amino, hydroxy, nitro,        cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy and        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo; and    -   R², R³, R⁴, R⁵, R⁶ and R⁷, which may be the same or different,        each independently represent hydrogen, C₁₋₆alkyl, amino,        hydroxy, halogen, or trifluoromethyl.

Such compound of Formula (Ig), wherein

-   -   R⁸ and R⁹ together with the carbon atoms to which they are        attached form a benzene ring system optionally substituted by        one to two substituents, which may be the same or different,        independently selected from halogen, amino, hydroxy, nitro,        cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy and        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo;    -   R², R³, R⁴ and R⁵, which may be the same or different,        independently represent hydrogen or methyl; and    -   R⁶ and R⁷ represent hydrogen.

Furthermore, a compound of Formula (Ig), wherein

-   -   R⁸ and R⁹ together with the carbon atoms to which they are        attached form a benzene ring system optionally substituted by        one to two substituents, which may be the same or different,        independently selected from halogen, amino, hydroxy, nitro,        cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy and        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo;    -   R², R³, R⁴ and R⁵, which may be the same or different,        independently represent hydrogen or ethyl or trifluoromethyl;        and    -   R⁶ and R⁷ represent hydrogen.

Such compound of Formula (Ig), wherein

-   -   R⁸ and R⁹ together with the carbon atoms to which they are        attached form a benzene ring system optionally substituted by        one to two substituents, which may be the same or different,        independently selected from halogen, amino, hydroxy, nitro,        cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy and        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo;    -   R⁶ and R⁷ represent hydrogen; and    -   one of R² and R³ represents methyl and the remaining of R² and        R³, and R⁴ and R⁵, represent hydrogen.

Furthermore, a compound of Formula (Ig), wherein

-   -   R⁸ and R⁹ together with the carbon atoms to which they are        attached form a benzene ring system optionally substituted by        one to two substituents, which may be the same or different,        independently selected from halogen, amino, hydroxy, nitro,        cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy and        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo;    -   R⁶ and R⁷ represent hydrogen; and    -   one of R² and R³ represents ethyl or trifluoromethyl and the        remaining of R² and R³, and R⁴ and R⁵, represent hydrogen.

Such a compound of Formula (Ig), wherein

-   -   R⁸ and R⁹ together with the carbon atoms to which they are        attached form an unsaturated cyclic ring system containing 5        carbon atoms, wherein 0 to 3 (i.e. 0, 1, 2 or 3) of the carbon        atoms of the ring formed by R⁸ and R⁹ may be replaced by a        heteroatom independently selected from nitrogen, oxygen and        sulfur and wherein the ring system may be optionally substituted        by one to two substituents, which may be the same or different,        independently selected from halogen, amino, hydroxy, nitro,        cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy,        C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonyloxy, C₁₋₆alkylamino,        di-C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, C₁₋₆alkylenedioxy,        aryl, heteroaryl, heterocyclyl, and cycloC₃₋₁₂alkyl;    -   R¹ represents chloro or bromo; and    -   R², R³, R⁴, R⁵, R⁶ and R⁷, which may be the same or different,        each independently represent hydrogen, C₁₋₆alkyl, amino,        hydroxy, halogen, or trifluoromethyl.

Such a compound of Formula (Ig), which is selected from those of Formula(IgA),

-   -   wherein    -   Y represents NH, S, or O;    -   R¹⁰ and R¹¹, which may be the same or different, each        independently represent hydrogen, halogen, amino, hydroxy,        nitro, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy, or        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo; and    -   R², R³, R⁴, R⁵, R⁶ and R⁷, which may be the same or different,        each independently represent hydrogen, C₁₋₆alkyl, amino,        hydroxy, halogen, or trifluoromethyl.

Such a compound of Formula (IgA),

-   -   wherein Y represents NH, S, or O;    -   R¹⁰ and R¹¹ which may be the same or different, each        independently represent hydrogen, halogen, amino, hydroxy,        nitro, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy, or        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo;    -   R², R³, R⁴ and R⁵, which may be the same or different,        independently represent hydrogen or methyl; and    -   R⁶ and R⁷ represent hydrogen.

Such a compound of Formula (IgA),

-   -   wherein Y represents NH, S, or O;    -   R¹⁰ and R¹¹, which may be the same or different, each        independently represent hydrogen, halogen, amino, hydroxy,        nitro, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyloxy, or        C₁₋₆alkylcarbonylamino;    -   R¹ represents chloro or bromo;    -   R⁶ and R⁷ represent hydrogen; and    -   one of R² and R³ represents methyl and the remaining of R² and        R³, and R⁴ and R⁵, represent hydrogen.

Furthermore, a compound selected from those of Formula (Ig)

-   -   wherein    -   R¹ represents chloro or bromo;    -   R², R³, R⁴, R⁵, R⁶ and R⁷, which may be the same or different,        each independently represent hydrogen, C₁₋₆alkyl, amino,        hydroxy, halogen, or trifluoromethyl;    -   R⁸ represents hydrogen, or C₁₋₆alkyl;    -   R⁹ represents aryl or heteroaryl, wherein the aryl or heteroaryl        group may be optionally substituted by one or more substituents        (e.g., 1, 2, or 3), which may be the same or different, selected        independently from halogen, amino, hydroxy, nitro, cyano,        trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy,        C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonyloxy, C₁₋₆alkylamino,        di-C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, C₁₋₆alkylenedioxy,        aryl, heteroaryl, heterocyclyl, and cycloC₃₋₁₂alkyl;    -   or R⁸ and R⁹ together with the carbon atoms to which they are        attached may form an unsaturated cyclic ring system containing 5        to 7 (i.e. 5, 6 or 7) carbon atoms, wherein 0 to 4 (i.e. 0, 1,        2, 3 or 4) of the carbon atoms of the ring system formed by R⁸        and R⁹ may be replaced by heteroatoms independently selected        from nitrogen, oxygen and sulfur and wherein the ring system may        be optionally substituted by one or more (e.g., 1, 2, or 3)        substituents, which may be the same or different, independently        selected from halogen, amino, hydroxy, nitro, cyano,        trifluoromethyl, trifluoromethoxy, aminocarbonyl,        N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy,        C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonyloxy, C₁₋₆alkylamino,        di-C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, C₁₋₆alkylenedioxy,        aryl, heteroaryl, heterocyclyl, and cycloC₃₋₁₂alkyl;        or an optical isomer, pharmaceutically acceptable salt, hydrate,        solvate, or polymorph thereof for use as a medicament.

In the compounds of the invention R¹ defined by Formula (Ig) and Formula(IgA) may represent bromo. Alternatively, R¹ defined by Formula (Ig) andFormula (IgA) may represent chloro. It will be apparent to those skilledin the art that the invention also includes optical isomers,pharmaceutically acceptable salts, hydrates, solvates, and polymorphs ofthe described compounds.

Moreover the invention deals with a pharmaceutical compositioncomprising, together with one or more pharmaceutically acceptableexcipients or vehicles, at least one compound of formula (Ig) or offormula (IgA), wherein the substituents are as defined above, or opticalisomers, pharmaceutically acceptable salts, hydrates, solvates, andpolymorphs thereof.

Moreover, a method for treating or preventing a condition or diseaseassociated with abnormal glutamate neurotransmission or a method formodulating mGluR5 receptors to achieve therapeutic benefit, or a methodfor enhancing cognition, such method comprising the step ofadministering to a living animal, including a human, a therapeuticallyeffective amount of a compound selected of those of formula (Ig) orformula (IgA).

Furthermore, the preparation of and the uses of a compound of formula(Ig) or formula (IgA) or optical isomers, pharmaceutically acceptablesalts, hydrates, solvates, and polymorphs thereof or the manufacturingor preparation of a medicament are part of the invention.

The invention in particular relates to a compound selected from those offormula (I)

-   -   wherein    -   R¹ represents chloro or bromo;    -   R² and R³ each independently represent hydrogen, C₁₋₆alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R² and R³ both together with the carbon atom of the ring        represent a carbonyl group;    -   R⁴ and R⁵ each independently represent hydrogen, C₁₋₆alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R⁴ and R⁵ both together with the carbon atom of the ring        represent a carbonyl group;    -   R⁶ and R⁷ independently represent hydrogen, C₁₋₆-alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R⁶ and R⁷ both together with the carbon atom of the ring        represent a carbonyl group;    -   R² or R³ together with R⁶ and R⁷ may also form a bivalent        radical selected from the group CH₂—CH₂ and CH₂—O;    -   R⁸ represents a radical R⁹ or a radical R¹⁰, whereby one of the        two radicals R⁸ represents R⁹ and the other radical R⁸        represents R¹⁰;    -   R⁹ represents a cyclic group selected from aryl, heteroaryl or        heterocyclyl, wherein the ring system may be optionally        substituted by one or two substituents, which may be the same or        different and selected independently from halogen, amino,        hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl and C₁₋₆alkoxy;    -   R¹⁰ represents hydrogen or C₁₋₆alkyl;    -   and optical isomers, pharmaceutically acceptable salts,        hydrates, solvates, and polymorphs thereof.

Such a compound of formula (I), wherein R², R³, R⁴, R⁵, R⁶ and R⁷independently represent hydrogen, C₁₋₆-alkyl, C₃₋₇cycloalkyl ortrifluoromethyl; and one of the radicals R⁸ represents hydrogen ormethyl and the other radical R⁸ represents a phenyl, thiophene, pyrrole,tetrazole, furane, pyridine or pyrimidine ring, wherein the ring systemmay be optionally substituted by one substituent selected from halogen,amino, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,C₁₋₆alkyl, hydroxyC₁₋₆alkyl and C₁₋₆alkoxy.

Such a compound of formula (I), wherein

R¹ represents chloro or bromo;

R² represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl;

R³ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl;

R⁴ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl;

R⁵ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl;

R⁶ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl;and

R⁷ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl.

Such a compound of formula (I), wherein

R¹ represents chloro or bromo;

R² represents hydrogen, C₁₋₆alkyl or trifluoromethyl;

R³ represents hydrogen, C₁₋₆alkyl or trifluoromethyl;

R⁴ represents hydrogen, C₁₋₆alkyl or trifluoromethyl;

R⁵ represents hydrogen, C₁₋₆alkyl or trifluoromethyl;

R⁶ represents hydrogen, C₁₋₆alkyl or trifluoromethyl; and

R⁷ represents hydrogen, C₁₋₆alkyl or trifluoromethyl.

Such a compound of formula (I), wherein

R¹⁰ is hydrogen.

Such a compound of formula (I), wherein

R¹⁰ is hydrogen and R⁹ is in 4-position of the tetrahydropyridine-ringand represents a substituted phenyl ring.

A further embodiment of the invention relates to compounds of formula(I), wherein R², R³, R⁴, R⁵, R⁶ and R⁷ independently represent hydrogen,C₁₋₆-alkyl, C₃₋₇cycloalkyl or trifluoromethyl; and one of the radicalsR⁸ represents hydrogen or methyl and the other radical R⁸ represents aphenyl, thiophene, pyrrole, tetrazole, furan, pyridine or pyrimidinering, wherein the ring system may be substituted by one substituentselected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,C₁₋₆alkyl and C₁₋₆alkoxy.

The invention also relates to a compound of formula (I), wherein one ofthe radicals R⁸ represents hydrogen and the other radical R⁸ representsa phenyl, thiophene, pyrrole, tetrazole, furan, pyridine or a pyrimidinering which may be optionally substituted by one substituent selectedfrom halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl,trifluoromethoxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl and C₁₋₆alkoxy.

A further embodiment of the invention relates to a compound of formula(I), wherein one of the radicals R⁸ represents hydrogen and the otherradical R⁸ represents a phenyl, thiophene, pyrrole, furan, pyridine orpyrimidine ring.

A further embodiment of the invention relates to a compound of formula(I), wherein R⁶ and R⁷ represent hydrogen.

A further embodiment of the invention relates to compound of formula(I), wherein R², R³, R⁴ and R⁵ independently represent hydrogen, methyl,ethyl or trifluoromethyl; and R⁶ and R⁷ represent hydrogen or methyl.

A further embodiment of the invention relates to compound of formula(I), wherein R², R³, R⁴, R⁵, R⁶ and R⁷ independently represent hydrogen,methyl or ethyl.

A further embodiment of the invention relates to compound of formula(I), wherein R² and R³ independently represent hydrogen, methyl orethyl. A further embodiment of the invention relates to compound offormula (I) wherein R² represent methyl or ethyl and R³ representhydrogen and which has at least one chiral carbon atom.

A further embodiment of the invention relates to compound of formula(I), wherein R² represent hydrogen or methyl and R³, R⁴, R⁵, R⁶ and R⁷represent hydrogen.

A further embodiment of the invention relates to compound of formula(I), wherein R¹ represents chloro.

A further embodiment of the invention relates to compound of formula(I), wherein R¹ represents bromo.

A further embodiment of the invention relates to a compound of formula(I), wherein R², R³, R⁴, R⁵, R⁶ and R⁷ represent hydrogen.

A further embodiment of the invention relates to a compound of formula(I), wherein R², R³, R⁴, R⁵, R⁶ and R⁷ represent hydrogen, and theradical R⁸ which is in 3-position of the dihydro-pyridin-ring systemalso represents hydrogen.

A further embodiment of the invention relates to a compound of formula(I), wherein the radical R⁸ which is in 4-position of thedihydro-pyridin-ring represents a phenyl, thiophene, pyrrole, tetrazole,furane, pyridine or pyrimidine ring, wherein the ring system may beoptionally substituted by one substituent selected from halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl and C₁₋₆alkoxy.

A further embodiment of the invention relates to a compound of formula(I), wherein the radical R⁸ which is in 3-position of thedihydro-pyridin-ring represents hydrogen, and the radical R⁸ which is in4-position of the dihydro-pyridin-ring represents a phenyl, thiophene,pyrrole, furane, pyridine or pyrimidine ring.

The invention includes compounds of formula (I) selected from thefollowing compounds (or salts thereof) and having the following chemicalnames:

-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone-   6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4′]bipyridinyl-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4′]bipyridinyl-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5′,6′-dihydro-2′H-[2,3′]bipyridinyl-1′-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5′,6′-dihydro-2′H-[2,3′]bipyridinyl-1′-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-thiophen-2-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-21H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-5-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2′-methyl-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2′-methyl-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-3,6-dihydro-2H-[4,4′]bipyridinyl-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-thiophen-2-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-2-methyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,6-dihydro-2H    pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   [4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(3-Bromo-phenyl)-3,6-dihydro-21H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(3-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   [4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   5    (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone-   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone    and optical isomers, polymorphs and pharmaceutically-acceptable acid    and base addition salts, hydrates, and solvates thereof.

The invention also relates to compounds of the formula (I) which aremarked by radioactive atoms. Typical compounds include those where oneor more hydrogens are substituted by tritium, where one or more C¹² aresubstituted by C¹⁴, where one or more fluor atoms are substituted by F¹⁸or other isotopes. These can be used for the treatment of diseases (e.g.cancer) but also for diagnostic purposes. The radioactive atomsexchanged in the molecule are often isotopes of carbon, hydrogen,halogen, sulphur or phosphor.

Moreover, the invention in general relates to the use of a metabotropicglutamate receptor modulator (and in particular of a mGluR5 modulator)for the preparation of a medicament and for the treatment of variousdiseases as mentioned hereunder in a mammal, including humans.

In particular, the invention relates to the use of a compound of formula(I) or of formula (Ia) as defined above or an optical isomer,pharmaceutically acceptable salt, hydrate, solvate or polymorph thereoffor the preparation of a medicament and for the treatment of a mammal,including humans.

Further, the invention relates to the use of a compound for thepreparation of a medicament for treating or preventing a condition ordisease associated with abnormal glutamate neurotransmission. Such a useincludes the use of a compound for the preparation of a medicament forthe prevention and/or treatment of a condition or disease in an animalincluding a human being which condition or disease is affected orfacilitated by the negative modulatory effect of mGluR5 modulators.

The invention is dealing with the use of a mGluR5 modulator and inparticular a compound according to formula (I), for the preparation of amedicament, including for the conditions or diseases selected from thosementioned earlier in the description.

The invention also relates to the use of a mGluR5 modulator, inparticular a compound according to formula (I), wherein the conditionassociated with abnormal glutamate neurotransmission is selected fromthose mentioned earlier in the description.

Further, the invention to the use of a compound wherein the conditionassociated with abnormal glutamate neurotransmission is selected from:neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, painrelated to rheumathic arthritis, inflammatory pain, L-dopa-induced andtardive dyskinesias, Parkinson's disease, anxiety disorders,Huntington's chorea, epilepsy, Alzheimer's disease, positive andnegative symptoms of schizophrenia, cognitive impairment, reflux,migraine or for cognitive enhancement and/or neuroprotection.

Further, the invention relates to a pharmaceutical compositioncomprising as active ingredient at least one compound of formula (I) asdefined above or an optical isomer, pharmaceutically acceptable salt,hydrate, solvate or polymorph thereof, together with one or morepharmaceutically acceptable excipients.

The invention also relates to the process for the synthesis orpreparation of a compound of formula (I)

-   -   wherein    -   R¹ represents chloro or bromo;    -   R² and R³ each independently represent hydrogen, C₁₋₆alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R² and R³ both together with the carbon atom of the ring        represent a carbonyl group;    -   R⁴ and R⁵ each independently represent hydrogen, C₁₋₆alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R⁴ and R⁵ both together with the carbon atom of the ring        represent a carbonyl group;    -   R⁶ and R⁷ independently represent hydrogen, C₁₋₆-alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R⁶ and R⁷ both together with the carbon atom of the ring        represent a carbonyl group;    -   R² or R³ together with R⁶ and R⁷ may also form a bivalent        radical selected from the group CH₂—CH₂ and CH₂—O;    -   R⁸ represents a radical R⁹ or a radical R¹⁰, whereby one of the        two radicals R⁸ represents R⁹ and the other radical R⁸        represents R¹⁰;    -   R⁹ represents an aryl, heteroaryl or heterocycle, wherein the        ring system may be optionally substituted by one or two        substituents, which may be the same or different and selected        independently from halogen, amino, hydroxyl, nitro, cyano,        trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl        and C₁₋₆alkoxy;    -   R¹⁰ represents hydrogen or C₁₋₆alkyl;        and optical isomers, pharmaceutically acceptable salts,        hydrates, solvates, and polymorphs thereof,    -   wherein a compound of formula (II)    -   is suspended in a mixture of ethanol and water and treated with        hydrochloric acid, followed by reaction with H₂NNHCOOCH₃ to        yield a compound of Formula (III)    -   which is reacted with a compound of Formula (IV)    -   to yield a compound of Formula (V)    -   which is hydrolyzed under acidic conditions to yield a compound        of Formula (VI)    -   which is treated with an amine of Formula (VII)    -   in the presence of a condensing agent, to yield a compound of        Formula (I), which is converted, if desired, to a        pharmaceutically acceptable salt, hydrate, solvate, or        polymorph.

A further embodiment of the invention relates to an amine compound offormula (VII)

-   -   wherein    -   R² and R³ each independently represent hydrogen, C₁₋₆alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R² and R³ both together with the carbon atom of the ring        represent a carbonyl group;    -   R⁴ and R⁵ each independently represent hydrogen, C₁₋₆alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R⁴ and R⁵ both together with the carbon atom of the ring        represent a carbonyl group;    -   R⁶ and R⁷ independently represent hydrogen, C₁₋₆-alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R⁶ and R⁷ both together with the carbon atom of the ring        represent a carbonyl group;    -   R² or R³ together with R⁶ and R⁷ may also form a bivalent        radical selected from the group CH₂—CH₂ and CH₂—O;    -   R⁸ represents a radical R⁹ or a radical R¹⁰, whereby one of the        two radicals R⁸ represents R⁹ and the other radical R⁸        represents R¹⁰;    -   R⁹ represents a cyclic group selected from aryl, heteroaryl or        heterocyclyl, wherein the ring system may be optionally        substituted by one or two substituents, which may be the same or        different and selected independently from halogen, amino,        hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl and C₁₋₆alkoxy;    -   R¹⁰ represents hydrogen or C₁₋₆alkyl.

A further embodiment of the invention relates to a process for thesynthesis of a compound of formula (I)

-   -   wherein    -   R¹ represents chloro or bromo;    -   R² and R³ each independently represent hydrogen, C₁₋₆alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R² and R³ both together with the carbon atom of the ring        represent a carbonyl group;    -   R⁴ and R⁵ each independently represent hydrogen, C₁₋₆alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R⁴ and R⁵ both together with the carbon atom of the ring        represent a carbonyl group;    -   R⁶ and R⁷ independently represent hydrogen, C₁₋₆-alkyl,        C₃₋₇cycloalkyl or trifluoromethyl; or    -   R⁶ and R⁷ both together with the carbon atom of the ring        represent a carbonyl group;    -   R² or R³ together with R⁶ and R⁷ may also form a bivalent        radical selected from the group CH₂—CH₂ and CH₂—O;    -   R⁸ represents a radical R⁹ or a radical R¹⁰, whereby one of the        two radicals R⁸ represents R⁹ and the other radical R⁸        represents R¹⁰;    -   R⁹ represents a cyclic group selected from aryl, heteroaryl or        heterocyclyl, wherein the ring system may be optionally        substituted by one or two substituents, which may be the same or        different and selected independently from halogen, amino,        hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl and C₁₋₆alkoxy;    -   R¹⁰ represents hydrogen or C₁₋₆alkyl;    -   and optical isomers, pharmaceutically acceptable salts,        hydrates, solvates, and polymorphs thereof,    -   wherein a compound of Formula (VIII)    -   is dissolved in an alcoholic solvent and treated with thionyl        chloride to yield a compound of Formula IX    -   wherein PG represents C₁₋₆alkyl, which is reduced under standard        conditions to yield a compound of Formula X    -   which is reacted with a compound of Formula (IV)    -   to yield a compound of Formula (XI)    -   which is hydrolyzed under acidic conditions to yield a compound        of Formula (VI)    -   which is treated with an amine of Formula (VII)    -   in the presence of a condensing agent, to yield a compound of        Formula (I), which is converted, if desired, to a        pharmaceutically acceptable salt, hydrate, solvate, or        polymorph.

Moreover, the mGluR modulators as described above are expected to have ahigh activity when administered in combination with other substancesexhibiting neurological effects via different mechanisms.

The invention also relates to a pharmaceutical composition comprising atleast two different active ingredients, containing at least one compoundof formula (I) as defined above, and furthermore containing at least oneNMDA receptor antagonist, together with one or more pharmaceuticallyacceptable excipients. These compositions can be used for the treatmentof CNS-related diseases, cognitive enhancement and for neuro-protection.

Simultaneous administration of Group I mGluR modulators and NMDAreceptor antagonists has also been shown to provide neuroprotection inanimal models (see e.g. Zieminska et al. Neurochemistry International,2006, 66, 301-309; Zieminska et al. Neurochemistry International, 2003,43, 481-492; Zieminska et al. Neurochemistry International, 2006, 48,491-497).

With respect to the specific compounds as described above, the combinedtherapy exhibits a greater neuroprotective effect than monotherapy witheither an mGluR modulator or an NMDA receptor antagonist. Asparticularly active NMDA receptor antagonist, the compound Memantine canbe named, which is also known as 1-amino-3,5-dimethyladamantane (seeU.S. Pat. No. 4,122,193; U.S. Pat. No. 4,273,774; and U.S. Pat. No.5,061,703).

Furthermore, the compound Neramexane, which also is known as1-amino-1,3,3,5,5-pentamethylcyclohexane, is a further active NMDAreceptor antagonist and is disclosed in detail in U.S. Pat. No.6,034,134 and U.S. Pat. No. 6,071,966. Memantine and Neramexane aresystemically-active noncompetitive NMDA receptor antagonists havingmoderate affinity for the receptor. They exhibit strong voltagedependent characteristics and fast blocking/unblocking kinetics (seee.g. Görtelmeyer et al., Arzneim-Forsch/Drug Res., 1992, 42:904-913;Winblad et al., Int. J. Geriat. Psychiatry, 1999, 14:135-146; Rogawski,Amino Acids, 2000, 19: 133-49; Danysz et al., Curr. Pharm. Des., 2002,8:835-43; Jirgensons et. al. Eur. J. Med. Chem., 2000, 35: 555-565).

The combination of NMDA antagonists with mGluR5 modulators can berealized in a single pharmaceutical composition (as principallydescribed in the prior art) comprising a mGluR5 modulator of the presentinvention and an NMDA receptor antagonist, in one pharmaceuticalformulation, or in two separate pharmaceutical compositions orformulations, one comprising a mGluR5 modulator of the present inventionand one comprising an NMDA receptor antagonist in a pharmaceuticalformulation, to be administered conjointly (simultaneously orsequentially).

For the sequential administration to be considered “conjoint”, however,the mGluR5 modulator of the present invention and the NMDA receptorantagonist must be administered separated by a time interval that stillpermits the resultant beneficial effect in a mammal. For example, themGluR5 modulator of the present invention and the NMDA receptorantagonist must be administered on the same day (e.g., each—once ortwice daily), preferably within an hour of each other, and mostpreferably simultaneously.

This invention also relates to a pharmaceutical composition comprising acombination of a compound of formula (I) as described above and an NMDAreceptor antagonist. Of particular interest is a composition, whereinthe NMDA receptor antagonist is selected from Memantine and Neramexane(or a combination thereof) and pharmaceutically acceptable salts,polymorphs, hydrates and solvates thereof.

The invention also relates to a pharmaceutical composition comprising atleast two different active ingredients, containing at least one compoundof formula (I) as defined above, and furthermore containing at least oneof L-DOPA, another dopaminomimetics (in particular an antiparkinsoniandopaminomimetics e.g. bromocriptine, cabergolin, ropinirole,pramiperole, pergolide, rotigotine), and a neuroleptic (in particular aclassical neuroleptic, e.g. haloperidol, perphenazin, chlorpromazine,metoclopramide).

These combination products can e.g. be used for the treatment ofCNS-related disorders and diseases. Because of the antidyskinetic effectof the compounds of formula (I), drug induced dyskinesias,neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias,dopaminomi-metic-induced dyskinesias can be treated in addition to theconditions which are typically treated with L-Dopa, dopaminomimetics orneuroleptics.

The invention also relates to a method of providing neuroprotection to aliving animal, including a human, comprising the step of administeringto a living animal, including a human, a therapeutically effectiveamount of a composition as described.

This invention is also dealing with the compounds of formula (I) for theuse as a medicament. Furthermore, the invention relates to the use of acompound of formula (I) for the manufacture of a medicament for thetreatment of the diseases and conditions mentioned above.

Furthermore, the invention relates to the use of a composition asdescribed for the manufacture of a medicament to provide neuroprotectionin an animal, including a human.

Furthermore, the invention relates to the use of a compound of formula(I) in the manufacture of a medicament for treatment of a conditionassociated with abnormal glutamate neurotransmission or in whichmodulation of mGluR5 receptors results in therapeutic benefit. Thedisorders which can be treated have already been described above. Suchconditions and indications include:

a) For mGluR5 modulators: chronic pain, neuropathic pain, diabeticneuropathic pain (DNP), cancer pain, pain related to rheumathicarthritis, inflammatory pain, L-dopa-induced dyskinesias,dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias inParkinson's disease therapy, dopaminomimetic-induced dyskinesias inParkinson's disease therapy, tardive dyskinesias, Parkinson's disease,anxiety disorders, panic disorders, anxiety and panic disorders, socialanxiety disorder (SAD), generalized anxiety disorder, substance-inducedanxiety disorder, eating disorders, obesity, binge eating disorders,Huntington's chorea, epilepsy, Alzheimer's disease, positive andnegative symptoms of schizophrenia, cognitive impairment, functionalgastrointestinal disorders, gastroesophageal reflux disease (GERD),migraine, irritable bowel syndrome (IBS), or for cognitive enhancementand/or neuroprotection.

b) For negative modulation of mGluR5: chronic pain, neuropathic pain,diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathicarthritis, inflammatory pain, L-dopa-induced dyskinesias,dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias inParkinson's disease therapy, dopaminomimetic-induced dyskinesias inParkinson's disease therapy, tardive dyskinesias, Parkinson's disease,anxiety disorders, panic disorders, anxiety and panic disorders, socialanxiety disorder (SAD), generalized anxiety disorder, substance-inducedanxiety disorder, eating disorders, obesity, binge eating disorders,migraine, irritable bowel syndrome (IBS), functional gastrointestinaldisorders, gastroesophageal reflux disease (GERD), Huntington's choreaand/or epilepsy.

c) For positive modulation of mGluR5: Alzheimer's disease, positiveand/or negative symptoms of schizophrenia, cognitive impairment, or forcognitive enhancement and/or neuroprotection.

The mGluR5 negative modulators in general and in particular thecompounds of formula (I) according to the invention can be used for thetreatment of binge eating disorders.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of the present invention, in the compounds of formula(I) the carbon atom content of various hydrocarbon-containing moietiesis indicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, i.e., the prefix C_(i-j) indicates a moietyof the integer “i” to the integer “j” carbon atoms, inclusive.

Thus, for example, (C₁₋₃)alkyl refers to alkyl of one to three carbonatoms (i.e. 1, 2 or 3 carbon atoms), inclusive, (methyl, ethyl, propyl,and isopropyl), straight and branched forms thereof, (C₁₋₆) for instancerefers to a radical of one to six carbon atoms (i.e. 1, 2, 3, 4, 5 or 6carbon atoms).

As used herein, the following definitions are applicable unlessotherwise described, the term “C₁₋₆alkyl” represents straight orbranched chain alkyl groups which may be optionally substituted by oneor more substituents selected from halogen, trifluoromethyl, C₁₋₆alkoxy,amino, hydroxy, C₁₋₆alkylamino, and di-(C₁₋₆alkyl)amino. Examples ofsuch alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl,tert-butyl, —CF₃, —C₂F₅, —CBr₃ and —CCl₃.

The term “C₂₋₆alkenyl” represents straight or branched chain alkenylgroups. The term “C₁₋₆alkoxy” represents straight or branched chain—O—C₁₋₆alkyl groups which may be optionally substituted by one or moresubstituents selected from halogen, trifluoromethyl, amino, hydroxy,C₁₋₆alkylamino and di-(C₁₋₆alkyl)amino. Examples of such alkoxy groupsinclude methoxy, ethoxy, n-propoxy, i-propoxy, —OCF₃ and —OC₂F₅.

The term “cycloC₃₋₁₂alkyl” represents monocyclic or bicyclic, ortricyclic alkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, bicyclo[2.2.1]heptyl and adamantanyl, which may beoptionally substituted by one or more substituents, which may be thesame or different, selected independently from halogen, trifluoromethyl,trifluoromethoxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, amino, hydroxy,nitro, cyano, cyanomethyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkylamino, anddi-(C₁₋₆alkyl)amino, C₁₋₆alkylcarbonylamino, and C₁₋₆alkylenedioxy.

The term “aryl” represents phenyl or naphthyl, wherein the phenyl ornaphthyl group is optionally substituted by one or more substituents,which may be the same or different, selected independently from halogen,trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl, hydroxyC₁₋₆alkylC₂₋₆alkenyl, C₁₋₆alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonyloxy, C₁₋₆alkylamino,di-(C₁₋₆alkyl)amino, C₁₋₆alkylcarbonylamino, aminocarbonyl,N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl, pyrrolidinyl,piperidinyl, morpholinyl, and piperazinyl, cycloC₃₋₁₂alkyl or optionallyC₁₋₆alkylenedioxy.

The term “acyl” includes —(C═O)-alkyl; —(C═O)aryl; —(C═O)-aralkyl,—(C═O)-heterocyclyl, C₁₋₆-alkylcarbonyl, C₃₋₇cycloalkylcarbonyl,C₂₋₆alkenylcarbonyl, C₂₋₆alkynylcarbonyl, arylcarbonyl,heteroarylcarbonyl or heterocyclylcarbonyl, wherein the terms alkyl,aryl and heterocyclyl are defied as above. Examples are acetyl,propionyl, benzoyl or pivaloyl.

The term “heteroaryl” represents an aromatic 5-6 membered ringcontaining from one to four heteroatoms selected from oxygen, sulfur andnitrogen, or a bicyclic group comprising a 5-6 membered ring containingfrom one to four heteroatoms selected from oxygen, sulfur and nitrogenfused with a benzene ring or a 5-6 membered ring containing from one tofour heteroatoms selected from oxygen, sulfur and nitrogen, wherein theheteroaryl group may be optionally substituted by one or moresubstituents, which may be the same or different, selected independentlyfrom halogen, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, amino, hydroxy, nitro, cyano,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonyloxy, C₁₋₆alkylamino, anddi-(C₁₋₆alkyl)amino, C₁₋₆alkylcarbonylamino, aminocarbonyl,N—C₁₋₆alkylaminocarbonyl, di-N,N—C₁₋₆alkylaminocarbonyl, pyrrolidinyl,piperidinyl, morpholinyl, cycloC₃₋₁₂alkyl, C₁₋₆alkylenedioxy and aryl.Representative heteroaryl groups include furanyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrazolyl, benzofuryl,benzothienyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinazolinyl,quinoxalinyl, cinnolinyl, naphtyridinyl, and isoquinolinyl. Examples arepyridyl, pyrimidyl, thienyl, furyl and others.

The term “heterocyclyl” represents a saturated or unsaturatednon-aromatic 3 to 12 membered ring comprising one to four heteroatomsselected from oxygen, sulfur and nitrogen, and a saturated orunsaturated non-aromatic bicyclic ring system having 3 to 12 memberscomprising one to six heteroatoms selected from oxygen, sulfur andnitrogen, wherein the heterocyclic ring or ring system is optionallysubstituted by one or more substituents selected independently from ahalogen, trifluoromethyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, amino,hydroxy, nitro, cyano, C₁₋₆alkoxycarbonyl, C₁₋₆alkylamino,di-C₁₋₆alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl,and aryl; examples of such heterocyclyl groups include piperidinyl,morpholinyl, thiomorpholinyl, imidazolidinyl, pyrazolidinyl,pyrrolidinyl, or piperazinyl, wherein the heterocyclic ring or ringsystem is linked to the group to which it is attached optionally vianitrogen or a carbon atom.

The term “halogen” represents fluorine, chlorine, bromine and iodine.

The compounds of the present invention are usually named according tothe IUPAC or CAS nomenclature system. Abbreviations which are well knownto one of ordinary skill in the art may be used (e.g. “Ph” for phenyl,“Me” for methyl, “Et” for ethyl, “h” for hour or hours, and “rt” forroom temperature).

The term “analog” or “derivative” is used herein in the conventionalpharmaceutical sense, to refer to a molecule that structurally resemblesa reference molecule, but has been modified in a targeted and controlledmanner to replace one or more specific substituents of the referentmolecule with an alternate substituent, thereby generating a moleculewhich is structurally similar to the reference molecule. Synthesis andscreening of analogs (e.g., using structural and/or biochemicalanalysis), to identify slightly modified versions of a known compoundwhich may have improved or biased traits (such as higher potency and/orselectivity at a specific targeted receptor type, greater ability topenetrate blood-brain barriers, fewer side effects, etc.) is a drugdesign approach that is well known in pharmaceutical chemistry.

In addition, using methods known to those skilled in the art, analogsand derivatives of the compounds of the invention can be created whichhave improved therapeutic efficacy, i.e., higher potency and/orselectivity at a specific targeted receptor type, either greater orlower ability to penetrate mammalian blood-brain barriers (e.g., eitherhigher or lower blood-brain barrier permeation rate), fewer sideeffects, etc.

The phrase “pharmaceutically acceptable”, as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to amammal (e.g., human). Preferably, as used herein, the term“pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopeia orother generally recognized pharmacopeia for use in mammals, and moreparticularly in humans.

Compounds of the present invention may be in the form ofpharmaceutically acceptable salts. “Pharmaceutically acceptable salts”refers to those salts which possess the biological effectiveness andproperties of the parent compound and which are not biologically orotherwise undesirable. The nature of the salt is not critical, providedthat it is non-toxic and does not substantially interfere with thedesired pharmacological activity.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically active, polymorphic, tautomeric, orstereoisomeric form, or mixture thereof, of a compound of the invention,which possesses the useful properties described herein.

All patents, applications, publications, test methods, literature, andother materials cited in this application are hereby incorporated byreference.

The following Schemes 1-3 describe the preparation of compounds ofFormula (I) of the present invention. All of the starting materials maybe prepared by procedures described in these schemes, by procedures wellknown to one of ordinary skill in organic chemistry, or may be obtainedcommercially. All of the final compounds of the present invention may beprepared by procedures described in these charts or by proceduresanalogous thereto, which would be well known to one of ordinary skill inorganic chemistry. All of the variables used in the schemes are asdefined below or as in the claims.

The compounds containing one or more chiral centers can be prepared asracemates or mixtures of various stereoisomers and then separated.However, they also can be prepared by a special enantioselectivesynthesis.

For several of the chiral compounds, the enantiomers differ inpharmacological activity.

Compounds of the present invention may be synthesized according toScheme 1.

5-Nitro-1H-pyrazole-3-carboxylic acid 1 is reduced under standardconditions, such as treatment with hydrogen in the presence ofpalladium(0) on carbon in a solvent such as methanol, to yield5-amino-1H-pyrazole-3-carboxylic acid 2. Compound 2 is reacted withdi-aldehyde 3, carrying a bromo or chloro substituent at the R¹position, under acid conditions, such as acetic acid, at elevatedtemperatures to give 6-bromo- or6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (4). A compound ofFormula I is prepared from 4 via reaction with an appropriate secondaryamine 5 in the presence of a condensation agent, including, for example,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(“TBTU”) or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC).

The amines (5) are commercially available or may be prepared accordingto literature procedures (see, for example, Bull. Soc. Chim. Belg., v.71, 1962; p. 592; US 2002/049223 A1 (2002/04/25); Chem. Ber., 84, 1951,p. 795-798; Bull. Soc. Chim. Fr. 5, 4, 1937, p. 1265-1269; Zh. Obshch.Khim., 7, 1937, p. 1999-2004; Chem. Pharm. Bull., EN, 31, 8, 1983, p.2583-2592; Tetrahedron, 28, 1972, p. 5999-6004; J. Org. Chem., 34, 8,1969, p. 2478; Pharm. Chem. J. (Engl. Tran.); 5; 5; 1971, p. 260;Khfzan; Khim. Famm. Zh., 5, 5, 1971, p. 13).

Compound 4 may also be prepared according to Scheme 2.

5-Nitro-3-pyrazole carboxylic acid 1 is dissolved in an alcoholicsolvent, e.g. methanol or ethanol, and reacted with thionyl chloride togive compound 1a bearing an alkyl ester group. The term “PG” denotes anyC₁₋₆ alkyl chain, including branched alkyl chains, for example, methyland ethyl groups. 5-Nitro-3-pyrazole-carboxylic acid alkyl ester 1a isreduced under standard conditions, such as treatment with hydrogen inthe presence of palladium(0) on carbon in a solvent such as methanol, toyield 5-amino-1H-pyrazole-3-carboxylic acid alkyl ester 2a. Compound 2ais reacted with di-aldehyde 3, carrying a bromo or chloro substituent atthe R¹ position, under acid conditions, such as acetic acid, at elevatedtemperatures to give 6-bromo- or6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid alkyl ester (4a).The ester 4a is hydrolyzed under acidic conditions such as sulphuricacid (30%) to yield 6-bromo- or6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid 4. A compound ofFormula I is prepared from 4 via reaction with an appropriate secondaryamine 5 as shown in Scheme 1.

Compound 4 may also be prepared according to Scheme 3.

Ethyl 3-cyano-2-oxopropionate sodium salt (“NaCOPE”) 6 is treated withmethyl hydrazino formiate to yield ethyl 5-aminopyrazole-3-carboxylate7. Compound 7 is reacted with dialdehyde 3, carrying a bromo or chlorosubstituent at the R¹ position, under acidic conditions, to yield ethyl6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylate 8. Theester 8 is hydrolyzed under acidic conditions to yield 6-bromo- or6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid 4. A compound ofFormula I is prepared from 4 via reaction with an appropriate secondaryamine 5 as shown in Scheme 1.

It will be appreciated that in the above transformations it may benecessary or desirable to protect any sensitive groups in the moleculeof the compound in question in order to avoid undesirable sidereactions.

EXPERIMENTAL PART

Hereinafter, “DMF” is defined as N,N-dimlethylformamide, “HCl” ashydrochloric acid, “DMSO” as dimethylsulfoxide and “TBTU” asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate.

Preparation 1 5-Nitro-3-pyrazole-carboxylic acid methyl ester

5-Nitro-3-pyrazol carboxylic acid (21.44 g, 136.5 mmol) is dissolved indry methanol (200 mL). Then, thionyl chloride (9.9 mL, 136.5 mmol) isadded slowly in a drop wise manner at RT. The reaction mixture is heatedover night under reflux and under argon atmosphere. After cooling down,the solvent is evaporated under vacuum and the crude material is heatedwith boiling hexane (200 ml). After cooling down and removal of thehexane, the material is washed two times with 200 ml pentane. Then, thesolvent is removed and the product is dried under vacuum to give5-nitro-3-pyrazole-carboxylic acid methyl ester (22.35 g, 95.7%).

Preparation 2 5-Amino-3-pyrazole-carboxylic acid methyl ester

5-Nitro-3-pyrazole-carboxylic acid methyl ester (22.35 g, 130.61 mmol)is dissolved in each 160 mL THF und glacial acetic acid. Then, Pd—C(10%, 4.36 g) are added and the reaction is stirred for 6 days underhydrogen atmosphere at RT. Then, the mixture is filtered over celite andthe solvent is removed under vacuum. The crude material is dissolved inmethylene chloride (800 mL) and sodium hydrogen carbonate (200 g) areadded, filtered and the solvent is again removed under vacuum. Thisprocedure is repeated until the acetic acid smell is lost.5-Amino-3-pyrazole-carboxylic acid methyl ester is isolated in highyields (16.91 g, 91.7%).

Preparation 3 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methylester

5-Amino-3-pyrazolcarboxylic acid methyl ester (16.91 g, 119.8 mmol) isdissolved in ethanol (2.4 L) and hydrochloric acid (37%, 12.5 mL, 150mmol) is added. Then, a solution of 2-bromo-malonealdehyde (18.9 g,125.2 mmol) is dissolved in ethanol (1.4 L) and is quickly added in adrop wise manner at RT. After 30 min, a precipitation is observed; after6 hours the precipitate is removed and washed with 50 ml ethanol andthereafter with 50 ml diethyl ether. Here, 4.19 g of the clean productare isolated. After evaporation of the filtrate and crystallisation,additional 1.43 g product are obtained to yield6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester (5.62g, 18.3% d. Th.). In case of a smaller scale reaction with only 1 g ofthe starting amine 5-amino-3-pyrazolcarboxylic acid methyl ester, theyield is much better e.g. 68%.

Preparation 4 6-Bromo-pyrazolo[1,5a]pyrimidine-2-carboxylic acid

6-Bromopyrazolo[1,5a]pyrimidin-2-carboxylic acid methyl ester (3.76 g,14.68 mmol) is heated in 600 mL water, 190 mL sulphuric acid (30%) and50 mL of the methanol/water mixture is removed from the reaction mixturevia distillation. After cooling down, 50 mL water is added, the mixtureis heated again and 50 mL of the alcohol-water mixture is removed. Thiscycle is repeated 6 times, the reaction mixture is cooled to RT andfiltered over a glass filter. The crude material is washed with water(100 mL), acetone (20 mL) and ether (20 mL) and dried under vacuum togive 6-Bromo-pyrazolo[1,5a]pyrimidine-2-carboxylic acid (2.61 g, 10.78mmol; 73.5%).

Physical characteristics are as follows: ¹H NMR (DMSO):

(ppm) 13.4, 9.7, 8.7, 7.2.

6-Chloro-pyrazolo[1,5a]pyrimidine-2-carboxylic acid

The hydrolysis of methyl 6-chloro-pyrazolo[1,5a]pyrimidine-2-carboxylateis performed under similar conditions as described above for methyl6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate.

Preparation 5 Ethyl 5-aminopyrazole-3-carboxylate

A 10 L three-necked flask is equipped with mechanical stirrer, refluxcondenser and nitrogen inlet. To ethyl 3-cyano-2-oxopropionate sodiumsalt (“NaCOPE”) (653.18 g; 4.0 mol), 585 mL of water, 3.6 L of ethanoland 350 mL of hydrochloric acid (12N; 4.2 mol) are added. The resultingsuspension is stirred at RT for 15 min. Then, methyl hydrazino formiate(356.0 g; 3.95 mol) is added as a solid material. A slightly exothermicreaction occurs. After the mixture is stirred at RT for 6 h, anotherportion of methyl hydrazino formiate (12.0 g; 133.7 mmol) is added andthe orange suspension is stirred at RT over night. Then potassiumcarbonate (K₂CO₃, 300.0 g; 2.17 mol) is added, followed by 250 mL ofwater. The internal temperature rises to 60° C. and a vigorous evolutionof gas starts. The mixture is heated at reflux for four hours. Aftercooling to RT, the alcohol is evaporated to yield a red paste, which istaken up in 1 L of water and 3 L of ethyl acetate. The aqueous phase isextracted with another 500 mL portion of ethyl acetate. The organicextracts are washed with brine and dried over sodium sulfate (Na₂SO₄).After filtration the solvent is evaporated to yield 330 g of a brownpaste. This crude product is mixed with 1 L of ether to give a lightbrown solid, which is separated from an orange liquid phase byfiltration. The solid is dried under vacuum to yield 229.12 g (7). Theliquid phase is evaporated; the residue is taken up in 250 mL of etherand cooled to −30° C. to yield another 15.09 g of 7. The total yield of7 is 244.21 g (1.57 mol; 39.3%). Physical characteristics are asfollows:

¹H-NMR (DMSO): δ (ppm) 1.26, 4.21, 5.0, 5.76, 12.12.

Preparation 6 Ethyl 6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate

A 2 L round bottom flask is charged with ethyl5-aminopyrazole-3-carboxylate (7) (44.92 g; 289.50 mmol), 1.2 L ofethanol and 27 mL of hydrochloric acid (12N; 324.0 mmol).2-Bromomalonaldehyde (43.71 g; 289.54 mmol) is added as a solid to theresulting yellow solution. A light brown solution is formed, from whicha tan solid started to precipitate after 15 min. The suspension isstirred at RT over night and thereafter, filtered with suction. Thesolid is washed with 200 mL of ether to yield 62.50 g of (8a) afterdrying at 40° C./1 Torr. Additional crystals are isolated from thefiltrate by concentration and cooling to −30° C. A total yield of 74.12g (274.4 mmol; 94.8%) of 8a is obtained with a HPLC-purity>97%.

Physical characteristics are: ¹H-NMR (DMSO): δ (ppm) 1.35, 4.39, 7.24,8.74, 9.68.

Preparation 7 Sodium Salt of Chloromalonaldehyde

A 2 L Schlenk flask equipped with a 500 mL addition funnel is chargedwith mucochloric acid (100.0 g; 592.0 mmol) dissolved in 400 mL ofethanol. Then, a solution of aniline (108 mL; 1.18 mmol) in 400 mL ofethanol is added over a period of 5 min. The reaction proceedsexothermic via the formation of large amounts of carbon dioxide.Thereafter, the orange solution is heated to reflux for 5 min and thencooled down to RT. Overnight, a yellow precipitate is formed. 500 mL ofHCl (1N) are added and the suspension is filtered with suction. Theresidue is washed with 200 mL of ethanol and 500 mL of ether. It isdried at 40° C./1 Torr to yield the hydrochloride of the dianilide (A)(107.8 g; 313.8 mmol; 53.7%) as a yellow solid which is used for thenext step without further purification. In a 10 L three necked flask, 5L of water are heated to reflux and the crude dianilide (A) (81.2 g;239.3 mmol) is added in 6 portions over 15 min. The foaming suspensionis heated for a further 15 min. Then, the mixture is cooled to RTovernight. After filtration with suction, the residue is suspended in150 mL of ethanol and treated in an ultrasonic bath for 2 min. Themixture is filtered again with suction and washed with 200 mL of ether.The pale yellow residue is dried at 40° C./1 Torr to yield 39.68 g ofthe monoanilide of chloromalonaldehyde (B) (218.5 mmol; 91.2%) with aHPLC-purity>97%. A 1 L round bottom flask is charged with 39.68 g (B)(218.5 mmol) and 200 mL of NaOH (2N solution). It is heated to refluxfor about 5 min until the solid is dissolved. At an internal temperatureof 45° C., ethyl acetate (40 mL) is added. The alkaline aqueous layer iswashed with a 40 mL portion of ethyl acetate and cooled to 5° C. After12 hrs, the colorless needles are filtered off and washed with 50 mL ofethanol and 200 mL of ether. Concentration and cooling of the motherliquor yielded another crop of crystals. In total, 29.16 g (159.7 mmol;73.1%) of the trihydrate of the sodium salt of chloromalonaldehyde (C)are isolated after drying at 40° C./1 Torr.

Preparation 8 Ethyl 6-chloro-pyrazolo[1,5a]pyrimidine-2-carboxylate

A 100 mL round bottom flask is charged with ethyl5-aminopyrazole-3-carboxylate (7) (2.0 g; 12.89 mmol) and 50 mL ofethanol. To this solution hydrogen chloride (12 N; 1.2 mL; 14.4 mmol) isadded. Then, the sodium salt of chloromalonaldehyde (C) (2.35 g; 12.89mmol) is added as a solid in one portion. The resulting suspension isstirred at RT over night. Thereafter, it is filtered with suction andwashed with 50 mL of ether. The residue is extracted with 120 mL ofchloroform in a soxleth apparatus for 5 h. Then, the solvent isevaporated from the organic extract yielding 2.44 g of 8b (10.8 mmol;83.9%) with >97% by HPLC.

Physical characteristics are: ¹H-NMR (DMSO):

(ppm) 1.35, 4.39, 7.25, 8.72, 9.63.

Preparation 9 6-Halogeno-pyrazolo[1,5a]pyrimidine-2-carboxylic acids

The hydrolysis of the ethyl6-halogeno-pyrazolo[1,5a]pyrimidine-2-carboxylates (8) with aqueousacids leads to the carboxylic acids (4) in good yields (>80%).Hydrochloric acid is used to hydrolyze the 6-chloro-ester. The6-bromo-derivative is hydrolyzed using sulfuric acid. In a typicalhydrolysis the compounds (8) are suspended in water and the acid isadded. Then, small amounts of alcohol-water-azeotrope are distilled offuntil no more ester is detected by TLC (MeCN+H2O=10+2, plate type:Alugram

SIL G/UV254). The suspensions are cooled by means of an ice-water bathand filtered with suction. The residues are washed with water, acetoneand ether. After drying at 40° C./1 Torr the6-halogenopyrazolo[1,5a]pyrimidine-2-carboxylic acids (6) are examinedby HPLC.

6-Bromo-pyrazolo[1,5a]pyrimidine-2-carboxylic acid

A 500 mL round bottom flask is charged with ethyl6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate (2.0 g; 7.41 mmol) and240 mL of water. After addition of diluted sulfuric acid (30 vol %; 62mL) the suspension is heated to reflux and 20 mL of anethanol-waterazeotrope is distilled off. 20 mL of water are added to thesuspension and another 20 mL portion is distilled off. After eight ofthese cycles, no more ester is detected by TLC. The mixture is cooled to10° C. by means of an ice-bath. It is filtered with suction and washedwith 100 mL of water, followed by 20 mL of acetone and 100 mL of ether.The residue is dried at 40° C./1 Torr to yield 1.54 g (6a) (6.36 mmol;83.5) as a beige powder.

Physical characteristics are as follows: ¹H-NMR (DMSO):

(ppm) 7.21, 8.75, 9.70, 13.44.

6-Chloro-pyrazolo[1,5a]pyrimidine-2-carboxylic acid

The hydrolysis of ethyl 6-chloro-pyrazolo[1,5a]pyrimidine-2-carboxylateis performed under similar conditions as described above for ethyl6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate.

Building Block Syntheses:

4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester

A solution of N-Boc-4-piperidone (2 mmol) in THF (4 mL) is cooled to−78° C. and a solution of LiHMDS (2.6 mmol) is added over 15 min. Thereaction mixture is stirred for 20 min. Tf₂NPh (2.4 mmol) solution inTHF (3 mL) is added at −78° C. and resulting mixture is stirred for 5min. Reaction vessel is then placed in an ice-bath and the mixture isstirred for additional 2 his. Solvent is evaporated in vacuo and thesolid residue is partitioned between water and methylene chloride.Organic phase is dried over anhydrous Na₂SO₄. Product obtained afterevaporation of organic phase is sufficiently pure for furthertransformation.

LC/MS: m/z=200 (MH⁺)

¹H NMR (CDCl₃) δ: 1.45, 2.42, 3.61, 4.02, 5.74.

3′,6′-Dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester

A solution of 1.68 mmol of 3-pyridyl boronic acid, 0.105 mmol ofPd[PPh₃]₄, and 0.84 mmol of4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester in 3 mL of THF is combined with 1.68 mmol of Na₂CO₃,2.52 mmol LiCl and 1 mL of water. The heterogenuous mixture is heated bymicrowaves at 120° C. for 30 min, and then partitioned between aqueoussodium carbonate solution and methylene chloride. The organic phase isseparated, dried over anhydrous Na₂SO₄ and evaporated in vacuo. Theresidue is purified by flash column chromatography to provide the titlecompound.

LC/MS: m/z=261 (MH⁺)

1′,2′,3′,6′-Tetrahydro-[3,4′]bipyridinyl

3′,6′-Dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester(0.2 mmol) is dissolved in a 20% mixture (1 mL) of trifluoroacetic acidin dry methylene chloride. The reaction solution is stirred for 1 h atroom temperature, and then evaporated in vacuo. The resulting amine saltis sufficiently pure for the next transformation.

LC/MS: m/z=161 (MH⁺)

2-Methyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid phenyl ester

A solution of 4-methoxypyridine (3.57 mmol) in THF (5 mL) is cooled to−30° C. MeMgCl solution (3.93 mmol) is then added followed by dropwiseaddition of ClCO₂Ph (3.93 mmol). The resulting reaction mixture isstirred for 30 min at −30° C., and acidified with 10% HCl solution. Themixture is allowed to warm up to room temperature and is extracted withethyl acetate. Combined organic phase is successively washed withsaturated bicarbonate and brine solution, and dried over anhydrousNa₂SO₄. The crude product obtained after evaporation of the solvent ispurified by flash column chromatography. Resulting colorless oilyproduct solidifies upon standing.

LC/MS: m/z=232 (MH⁺)

¹H NMR (CDCl₃) δ: 1.38, 2.40, 2.97, 4.87, 5.44, 7.15-7.46, 7.87.

2-Methyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid phenyl ester

L-Selectride (0.26 mmol) solution is added dropwise to2-Methyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid phenyl ester(0.22 mmol) in THF (2 mL) at −78° C. The resulting solution is stirredfor 2 hrs. Tf₂NPh (0.29 mmol) is added at −35° C. and the solution isstirred for another 2 hrs. Solvent is evaporated in vacuo and the solidresidue is partitioned between water and methylene chloride. Organicphase is dried over anhydrous Na₂SO₄. The crude product obtained afterevaporation of the solvent is purified by flash column chromatography.Resulting product appears as a single isomer as evidenced by gaschromatography.

LC/MS: m/z=366 (MH⁺)

¹H NMR (CDCl₃) δ: 1.31, 2.17, 2.94, 3.88, 4.65, 4.87, 6.96-7.48.

6-Methyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid phenyl ester

L-Selectride (0.21 mmol) solution is added dropwise to2-Methyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid phenyl ester(0.22 mmol), in THF (2 mL) at −78° C. The resulting solution is stirredfor 2 hrs. Tf₂NPh (0.29 mmol) is added at 0° C. and the solution isstirred for another 2 hrs. Solvent is evaporated in vacuo and the solidresidue is partitioned between water and methylene chloride. Organicphase is dried over anhydrous Na₂SO₄. The crude product obtained afterevaporation of the solvent is purified by flash column chromatography.Resulting product is a mixture of isomeric triflates in a ratio 4:1 asevidenced by gas chromatography.

LC/MS: m/z=366 (MH⁺)

¹H NMR (CDCl₃) δ: 1.32, 2.32, 2.61-2.83, 3.07-3.36, 4.40, 4.81-4.95,5.79, 7.09-7.42.

2-Methyl-4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid phenyl ester

A solution of 0.55 mmol of phenyl boronic acid, 0.035 mmol of Pd[PPh₃]₄,and 0.27 mmol of2-methyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid phenyl ester in 5 mL of THF is combined with 0.55 mmol of K₂CO₃,and 1 mL of water. The heterogeneous mixture is heated by microwaves at120° C. for 30 min, and then partitioned between aqueous sodiumcarbonate solution and methylene chloride. The organic phase isseparated, dried over anhydrous Na₂SO₄ and evaporated in vacuo. Theresidue is purified by flash column chromatography to provide the titlecompound.

LC/MS: m/z=294 (MH⁺)

¹H NMR (CDCl₃) δ: 1.24, 2.31, 2.87, 3.88, 4.52, 4.78, 6.01, 7.02-7.41.

2-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine

2-Methyl-4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid phenyl esteris dissolved in a mixture of 2 mL of isopropyl alcohol and 2 mL of 2 Maqueous LiOH solution. The resulting reaction mixture is refluxed for 48hrs. The solution is concentrated in vacuo and extracted with diethylether. Combined organic phase is washed with brine and dried over NaOHpellets. Solvent is evaporated and resulting product is used withoutfurther purification.

LC/MS: m/z=174 (MH⁺)Final Coupling Reaction General Scheme:

Acid A (1 equiv., 0.4 mmol) is mixed with TBTU (1.1 equiv., 0.145 g,0.45 mmol) in dry CH₃CN. Then, Et₃N (2.5 equiv., 0.14 mL, 1 mmol) isadded. The corresponding amine (1 equiv., 0.4 mmol) is added. Thereaction is stirred at 50° C. for 2 h to adjust full resolution of theacid. Then, the reaction is carried out at room temperature. Thereaction is monitored with TLC. When the reaction is over, some water isadded to the reaction mixture. If a precipitate formed it is filteredoff, washed with 5% ammonia solution and ether. If an oil formed it isextracted with methylene chloride and separated on a column (differentsystems) providing the final compounds in good to moderate yields.

The following compounds according to the invention are prepared asexamples, which are intended as an illustration of and not a limitationupon the scope of the invention:

Example 1(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

To a solution of 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid(0.7 g, 2.9 mmol, 1.0 equiv) and TBTU (1.0 g, 3.1 mmol, 1.1 equiv) indry CH₃CN (20 mL), triethylamine (1 mL, 7.25 mmol, 2.5 equiv) and4-phenyl-1,2,3,6-tetrahydro-pyridine (0.56 g, 2.9 mmol, 1 equiv) areadded. The reaction mixture is stirred at 50° C. for 2 h and then atroom temperature for 8 h. The reaction mixture is diluted with water (10mL). The precipitate is filtered off, washed sequentially with 50%aqueous ethanol, water, 5% aqueous ammonia, and diethyl ether and driedto provide 0.539 g of the title compound.

Yield: 48%

LC/MS: m/z=383 (MH⁺)

¹H NMR (d₆-DMSO) δ: 2.58, 3.89, 4.31 4.42, 6.09 6.23, 7.02, 7.25, 7.34,7.43, 8.68, 9.58.

Example 26-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-phenyl-1,2,3,6-tetrahydro-pyridine to provide the title compound inmoderate yield.

LC/MS: m/z=339 (MH⁺)

Example 3(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl to provide the title compoundin moderate yield.

LC/MS: m/z=340 (MH⁺)

Example 46-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with5-Phenyl-1,2,3,6-tetrahydro-pyridine to provide the title compound inmoderate yield.

LC/MS: m/z=384 (MH⁺)

Example 5(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl to provide the title compoundin moderate yield.

LC/MS: m/z=385 (MH⁺)

Example 6(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1′,2′,3′,6′-tetrahydro-[3,4′]bipyridinyl to provide the title compoundin moderate yield.

LC/MS: m/z=340 (MH⁺)

Example 7(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1′,2′,3′,6′-tetrahydro-[3,4′]bipyridinyl to provide the title compoundin moderate yield.

LC/MS: m/z=385 (MH⁺)

¹H NMR (CDCl₃) δ: 8.83-8.50, 7.92-7.66, 7.46-7.10, 6.10, 4.53, 4.08,2.66.

Example 8(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4′]bipyridinyl-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1,2,3,6-tetrahydro-[4,4′]bipyridinyl to provide the title compound inmoderate yield.

LC/MS: m/z=340 (MH⁺)

Example 9(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4′]bipyridinyl-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1,2,3,6-tetrahydro-[4,4′]bipyridinyl to provide the title compound inmoderate yield.

LC/MS: m/z=385 (MH⁺)

Example 10(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1,2,5,6-tetrahydro-[3,4′]bipyridinyl to provide the title compound inmoderate yield.

LC/MS: m/z=385 (MH⁺)

Example 11(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1,2,5,6-tetrahydro-[3,4′]bipyridinyl to provide the title compound inmoderate yield.

LC/MS: m/z=340 (MH⁺)

Example 12

(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1,2,5,6-tetrahydro-[3,3′]bipyridinyl to provide the title compound inmoderate yield.

LC/MS: m/z=385 (MH⁺)

Example 13(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1,2,5,6-tetrahydro-[3,3′]bipyridinyl to provide the title compound inmoderate yield.

LC/MS: m/z=340 (MH⁺)

Example 14(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5′,6′-dihydro-2′H-[2,3′]bipyridinyl-1′-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1′,2′,5′,6′-tetrahydro-[2,3′]bipyridinyl to provide the title compoundin moderate yield.

LC/MS: m/z=385 (MH⁺)

Example 15(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5′,6′-dihydro-2′H-[2,3′]bipyridinyl-1′-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with1′,2′,5′,6′-tetrahydro-[2,3′]bipyridinyl to provide the title compoundin moderate yield.

LC/MS: m/z=340 (MH⁺)

Example 16(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-thiophen-2-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-thiophen-2-yl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=345 (MH⁺)

Example 17(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-furan-2-yl-1,2,3,6-tetrahydro-pyridine to provide the title compoundin moderate yield.

LC/MS: m/z=329 (MH⁺)

Example 18(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(1H-pyrrol-2-yl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=328 (MH⁺)

Example 19(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(1-methyl-1H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=342 (MH⁺)

Example 20(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(1-methyl-1H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=387 (MH⁺)

Example 21(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=398 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 22(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-5-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-5-phenyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: In/z=398 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 23(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=353 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 24(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2′-methyl-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2′-Methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl to provide the titlecompound in moderate yield.

LC/MS: m/z=354 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 25(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2′-methyl-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2′-Methyl-1′,2′,3′,6′-tetrahydro-[3,4′]bipyridinyl to provide the titlecompound in moderate yield.

LC/MS: m/z=354 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 26(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-3,6-dihydro-2H-[4,4′]bipyridinyl-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-1,2,3,6-tetrahydro-[4,4′]bipyridinyl to provide the titlecompound in moderate yield.

LC/MS: m/z 354 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 27(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-thiophen-2-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-thiophen-2-yl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=359 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 28(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-2-methyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-Furan-2-yl-2-methyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=343 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 29(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-(1H-pyrrol-2-yl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=342 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 30(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=398 (MH⁺)

¹H NMR (CDCl₃) δ: 8.83, 8.54, 7.38-7.30, 7.05, 6.12-5.95, 5.03-4.75,4.21-3.83, 3.02-2.92, 2.44-2.28, 1.33-1.25.

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 31(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=353 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 32(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-methyl-4-(2-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=443 (MH⁺)

¹H NMR (CDCl₃) δ: 8.81, 8.54, 7.90, 7.58-7.30, 7.06, 5.74-5.34,5.02-4.71, 3.87-3.77, 2.90-2.81, 1.43-1.40.

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 33(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-methyl-4-(2-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=398 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 34(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-methyl-4-(3-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=443 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 35(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-methyl-4-(4-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=443 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 36(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-methyl-4-(3-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=398 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 37(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-methyl-4-(4-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=398 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 38(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=429 (MH⁺)

Example 39(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=429 (MH⁺)

Example 40(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]n-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=429 (MH⁺)

Example 41(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=384 (MH⁺)

Example 42(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=384 (MH⁺)

Example 43(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=384 (MH⁺)

Example 44(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Fluoro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=416 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 45(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Fluoro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=416 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 46(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Fluoro-phenyl)-2-methyl-1,1,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=416 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 47(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Fluoro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=371 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 48(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Fluoro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=371 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 49(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Fluoro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=371 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 50(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=402 (MH⁺)

Example 51(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=402 (MH⁺)

Example 52(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=402 (MH⁺)

Example 53(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=357 (MH⁺)

Example 54(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=357 (MH⁺)

Example 55(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=357 (MH⁺)

Example 56[4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=477 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 57[4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=477 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 58[4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=477 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 59[4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 64,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=432 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 60[4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=432 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 61[4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Bromo-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=432 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 62[4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=463 (MH⁺)

Example 63[4-(3-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=463 (MH⁺)

Example 64[4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=463 (MH⁺)

Example 65[4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=418 (MH⁺)

Example 66[4-(3-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=418 (MH⁺)

Example 67[4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Bromo-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=418 (MH⁺)

Example 68(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=432 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 69(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=432 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 70(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=432 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 71(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=388 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 72(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=388 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 73(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Chloro-phenyl)-2-methyl-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=388 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 74(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=418 (MH⁺)

Example 75(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=418 (MH⁺)

Example 76(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=418 (MH⁺)

Example 77(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=374 (MH⁺)

Example 78(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=374 (MH⁺)

Example 79(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Chloro-phenyl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=374 (MH⁺)

Example 80(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-(2-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine toprovide the title compound in moderate yield.

LC/MS: m/z=466 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 81(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine toprovide the title compound in moderate yield.

LC/MS: m/z=466 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 82(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine toprovide the title compound in moderate yield.

LC/MS: m/z=466 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 83(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-(2-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine toprovide the title compound in moderate yield.

LC/MS: m/z=421 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 84(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine toprovide the title compound in moderate yield.

LC/MS: m/z=421 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 85(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine toprovide the title compound in moderate yield.

LC/MS: m/z=421 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 86(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=452 (MH⁺)

Example 87(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=452 (MH⁺)

Example 88(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=452 (MH⁺)

Example 89(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=407 (MH⁺)

Example 90(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(3-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=407 (MH⁺)

Example 91(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(4-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=407 (MH⁺)

Example 92(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-(1H-tetrazol-5-yl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=390 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 93(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-(1H-tetrazol-5-yl)-1,2,3,6-tetrahydro-pyridine to provide thetitle compound in moderate yield.

LC/MS: m/z=345 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 94(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(1H-Tetrazol-5-yl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=376 (MH⁺)

Example 95(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(1H-Tetrazol-5-yl)-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=331 (MH⁺)

Example 96(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine to provide thetitle compound in moderate yield.

LC/MS: m/z=355 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 97(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(2-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine to provide thetitle compound in moderate yield.

LC/MS: m/z=400 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 98(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrimidine to provide the titlecompound in moderate yield.

LC/MS: m/z=341 (MH⁺)

Example 99(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrimidine to provide the titlecompound in moderate yield.

LC/MS: m/z=386 (MH⁺)

Example 100(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with5-(2-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine to provide thetitle compound in moderate yield.

LC/MS: m/z=355 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 101(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with5-(2-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine to provide thetitle compound in moderate yield.

LC/MS: m/z=400 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 102(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with5-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrimidine to provide the titlecompound in moderate yield.

LC/MS: m/z=341 (MH⁺)

Example 103(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with5-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrimidine to provide the titlecompound in moderate yield.

LC/MS: m/z=386 (MH⁺)

Example 104(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-o-tolyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=412 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 105(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-m-tolyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=412 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 106(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-p-tolyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=412 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 107(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-o-tolyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=367 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 108(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-m-tolyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=367 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 109(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with2-Methyl-4-p-tolyl-1,2,3,6-tetrahydro-pyridine to provide the titlecompound in moderate yield.

LC/MS: m/z=367 (MH⁺)

The stereo-isomers of this compound are separated. The S-configuratedcompound has a different activity than the R-configurated isomer.

Example 110(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-o-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title compound inmoderate yield.

LC/MS: m/z=398 (MH⁺)

Example 111(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-m-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title compound inmoderate yield.

LC/MS: m/z=398 (MH⁺)

Example 112(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-p-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title compound inmoderate yield.

LC/MS: m/z=398 (MH⁺)

Example 113(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-o-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title compound inmoderate yield.

LC/MS: m/z=353 (MH⁺)

Example 114(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-m-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title compound inmoderate yield.

LC/MS: m/z=353 (MH⁺)

Example 115(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

In analogy to the procedure described in Example 1,6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with4-p-Tolyl-1,2,3,6-tetrahydro-pyridine to provide the title compound inmoderate yield.

LC/MS: m/z=353 (MH⁺)

The pure stereoisomeric forms (including optical isomers) of thecompounds and the intermediates of this invention may be obtained by theapplication of art-known procedures. Diastereomers may be separated byphysical separation methods such as selective crystallization andchromatographic techniques, e.g. liquid chromatography using chiralstationary phases. Enantiomers (optically active isomers) may beseparated from each other by selective crystallization of theirdiastereomeric salts with optically active acids. Alternatively,enantiomers may be separated by chromatographic techniques using chiralstationary phases.

Said pure stereoisomeric forms may also be derived from thecorresponding pure stereoisomeric form of appropriate startingmaterials, provided that the reaction occur stereoselectively.Stereoisomeric forms of Formula (I) are included within the scope ofthis invention.

For therapeutic use, salts of the compounds of Formula I are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases, which are non-pharmaceutically acceptable, may alsofind use, for example, in the preparation and purification ofpharmaceutically acceptable compounds. All salts whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable salts as mentioned above are meant tocomprise the therapeutically active non-toxic salt forms, which thecompounds of formula I are able to form. The latter can conveniently beobtained by treating the base form with such appropriate acids asinorganic acids, e.g. hydrohalic acids such as hydrochloric, hydrobromicand the like; sulfuric acid; nitric acid; phosphoric acid and the like;or organic acids such as acetic, propanoic, hydroxyacetic,2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic,fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic, cyclohexane-sulfonic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic and the like acids. Conversely, the salt formcan be converted by treatment with alkali into the free base form.

Pharmaceutical Compositions

The active ingredients of formula (I) of the invention, together withone or more conventional adjuvants, carriers, or diluents, may be placedinto the form of pharmaceutical compositions and unit dosages thereof,and in such form may be employed as solids, such as coated or uncoatedtablets or filled capsules, or liquids, such as solutions, suspensions,emulsions, elixirs, or capsules filled with the same, all for oral use;in the form of suppositories or capsules for rectal administration or inthe form of sterile injectable solutions for parenteral (includingintravenous or subcutaneous) use.

Such pharmaceutical compositions and unit dosage forms thereof maycomprise conventional or new ingredients in conventional or specialproportions, with or without additional active compounds or principles,and such unit dosage forms may contain any suitable effective amount ofthe active ingredient commensurate with the intended daily dosage rangeto be employed. Tablets containing one (1) to one hundred (100)milligrams of active ingredient or, more broadly, zero point five (0.5)to five hundred (500) milligrams per tablet, are accordingly suitablerepresentative unit dosage forms.

The term “carrier” applied to pharmaceutical compositions of theinvention refers to a diluent, excipient, or vehicle with which anactive compound is administered. Such pharmaceutical carriers can besterile liquids, such as water, saline solutions, aqueous dextrosesolutions, aqueous glycerol solutions, and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. A. R. Gennaro,20^(th) Edition, describes suitable pharmaceutical carriers in“Remington: The Science and Practice of Pharmacy”.

Method of Treating and Pharmaceutical Formulations

Due to their high degree of activity and their low toxicity, togetherpresenting a most favorable therapeutic index, the active principles offormula (I) of the invention may be administered to a subject, e.g., aliving animal (including a human) body, in need thereof, for thetreatment, alleviation, or amelioration, palliation, or elimination ofan indication or condition which is susceptible thereto, orrepresentatively of an indication or condition set forth elsewhere inthis application, preferably concurrently, simultaneously, or togetherwith one or more pharmaceutically-acceptable excipients, carriers, ordiluents, especially and preferably in the form of a pharmaceuticalcomposition thereof, whether by oral, rectal, or parental (includingintravenous and subcutaneous) or in some cases even topical route, in aneffective amount. Suitable dosage ranges are 1-1000 milligrams daily,preferably 10-500 milligrams daily, and especially 50-500 milligramsdaily, depending as usual upon the exact mode of administration, form inwhich administered, the indication toward which the administration isdirected, the subject involved and the body weight of the subjectinvolved, and the preference and experience of the physician orveterinarian in charge.

The term “therapeutically effective” applied to dose or amount refers tothat quantity of a compound or pharmaceutical composition that issufficient to result in a desired activity upon administration to aliving animal body in need thereof.

The active agents of formula (I) of the present invention may beadministered orally, topically, parenterally, or mucosally (e.g.,buccally, by inhalation, or rectally) in dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptable carriers.It is usually desirable to use the oral route. The active agents may beadministered orally in the form of a capsule, a tablet, or the like (seeRemington: The Science and Practice of Pharmacy, 20^(th) Edition). Theorally administered medicaments may be administered in the form of atime-controlled release vehicle, including diffusion-controlled systems,osmotic devices, dissolution-controlled matrices, anderodible/degradable matrices.

For oral administration in the form of a tablet or capsule, the activedrug component of formula (I) may be combined with a non-toxic,pharmaceutically acceptable excipients such as binding agents (e.g.,pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol,sorbitol and other reducing and non-reducing sugars, microcrystallinecellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc, or silica, steric acid, sodium stearylfumarate, glyceryl behenate, calcium stearate, and the like);disintegrants (e.g., potato starch or sodium starch glycolate); orwetting agents (e.g., sodium lauryl sulphate), coloring and flavoringagents, gelatin, sweeteners, natural and synthetic gums (such as acacia,tragacanth or alginates), buffer salts, carboxymethylcellulose,polyethyleneglycol, waxes, and the like. For oral administration inliquid form, the drug components may be combined with non-toxic,pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol,water), suspending agents (e.g., sorbitol syrup, cellulose derivativesor hydrogenated edible fats), emulsifying agents (e.g., lecithin oracacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol or fractionated vegetable oils), preservatives (e.g., methyl orpropyl-p-hydroxybenzoates or sorbic acid), and the like. Stabilizingagents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate,citric acid) may also be added to stabilize the dosage forms.

The tablets containing as active compound a compound of formula (I) maybe coated by methods well known in the art. The compositions of theinvention containing as active compound a compound of formula (I) may bealso introduced in beads, microspheres or microcapsules, e.g.,fabricated from polyglycolic acid/lactic acid (PGLA). Liquidpreparations for oral administration may take the form of, for example,solutions, syrups, emulsions or suspensions, or they may be presented asa dry product for reconstitution with water or other suitable vehiclebefore use. Preparations for oral administration may be suitablyformulated to give controlled or postponed release of the activecompound.

The active drugs of formula (I) may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines, as is well known.

Drugs of the invention containing as active compound a compound offormula (I) may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Activedrugs may also be coupled with soluble polymers as targetable drugcarriers. Such polymers include polyvinyl-pyrrolidone, pyran copolymer,polyhydroxy-propyl methacrylamide-phenol,polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, active drug may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals,polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

For administration by inhalation, the therapeutics according to thepresent invention containing as active compound a compound of formula(I) may be conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide, orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator can be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The formulations of the invention containing a compound of formula (I)may be delivered parenterally, i.e., by intravenous (i.v.),intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal(i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.)administration, by direct injection, via, for example, bolus injectionor continuous infusion. Formulations for injection can be presented inunit dosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions can take such forms as excipients,suspensions, solutions, or emulsions in oily or aqueous vehicles, andcan contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredient can be in powderform for reconstitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

Compositions of the present invention containing a compound of formula(I) may also be formulated for rectal administration, e.g., assuppositories or retention enemas (e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides).

The compositions containing a compound of formula (I) may, if desired,be presented in a pack or dispenser device, which may contain one ormore unit dosage forms containing the active ingredient and/or maycontain different dosage levels to facilitate dosage titration. The packmay, for example, comprise metal or plastic foil, such as a blisterpack. The pack or dispenser device may be accompanied by instructionsfor administration. Compositions of the invention formulated in acompatible pharmaceutical carrier may also be prepared, placed in anappropriate container, and labeled for treatment of an indicatedcondition.

As disclosed herein, the dose of the components in the compositions ofthe present invention is determined to ensure that the dose administeredcontinuously or intermittently will not exceed an amount determinedafter consideration of the results in test animals and the individualconditions of a patient. A specific dose naturally varies depending onthe dosage procedure, the conditions of a patient or a subject animalsuch as age, body weight, sex, sensitivity, feed, dosage period, drugsused in combination, seriousness of the disease. The appropriate doseand dosage times under certain conditions can be determined by the testbased on the above-described indices but may be refined and ultimatelydecided according to the judgment of the practitioner and each patient'scircumstances (age, general condition, severity of symptoms, sex, etc.)according to standard clinical techniques.

Toxicity and therapeutic efficacy of the compositions of the inventioncan be determined by standard pharmaceutical procedures in experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between therapeutic and toxic effects isthe therapeutic index and it may be expressed as the ratio ED₅₀/LD₅₀.Compositions that exhibit large therapeutic indices are preferred.

Examples of Representative Pharmaceutical Compositions

With the aid of commonly used solvents, auxiliary agents and carriers,the reaction products can be processed into tablets, coated tablets,capsules, drip solutions, suppositories, injection and infusionpreparations, and the like and can be therapeutically applied by theoral, rectal, parenteral, and additional routes. Representativepharmaceutical compositions containing a compound of formula (I)according to the present invention follow:

(a) Tablets suitable for oral administration which contain the activeingredient, may be prepared by conventional tabletting techniques.

(b) For suppositories, any usual suppository base may be employed forincorporation thereinto by usual procedure of the active ingredient,such as a polyethyleneglycol which is a solid at normal room temperaturebut which melts at or about body temperature.

(c) For parental (including intravenous and subcutaneous) sterilesolutions, the active ingredient together with conventional ingredientsin usual amounts are employed, such as for example sodium chloride anddouble-distilled water q.s., according to conventional procedure, suchas filtration, aseptic filling into ampoules or IV-drip bottles, andautoclaving for sterility.

Formulation Examples for the Compounds of Formula (I)

The following examples are given by way of illustration. As activeingredient, the compound according to example 1 can be used.

Example 1 Tablet Formulation

A suitable formulation for a tablet containing 10 milligrams of activeingredient is as follows: mg Active Ingredient 10 Lactose 61Microcrystalline Cellulose 25 Talcum 2 Magnesium stearate 1 Colloidalsilicon dioxide 1

Example 2 Coated Tablet Formulation

Another suitable formulation for a tablet containing 100 mg is asfollows: mg Active Ingredient 100 Polyvinylpyrrolidone, crosslinked 10Potato starch 20 Polyvinylpyrrolidone 19 Magnesium stearate 1Microcrystalline Cellulose 50 Film coated and colored. The film coatingmaterial consists of: Hypromellose 10 Microcryst. Cellulose 5 Talcum 5Polyethylene glycol 2 Color pigments 5

Example 3 Capsule Formulation

A suitable formulation for a capsule containing 50 milligrams of activeingredient is as follows: mg Active Ingredient 50 Corn starch 26 Dibasiccalcium phosphate 50 Talcum 2 Colloidal silicon dioxide 2

This formulation is filled in a gelatin capsule.

Example 4 Solution for Injection

A suitable formulation for an injectable solution is as follows: ActiveIngredient mg 10 Sodium chloride mg q.s. Water for Injection ml add 1.0

Example 5 Liquid Oral Formulation

A suitable formulation for 1 liter of an oral solution containing 2milligrams of active ingredient in one milliliter of the mixture is asfollows: mg Active Ingredient 2 Saccharose 250 Glucose 300 Sorbitol 150Orange flavor 10 Colorant q.s. Purified water add 1000 ml

Example 6 Liquid Oral Formulation

Another suitable formulation for 1 liter of a liquid mixture containing20 milligrams of active ingredient in one milliliter of the mixture isas follows: g Active Ingredient 20.00 Tragacanth 7.00 Glycerol 50.00Saccharose 400.00 Methylparaben 0.50 Propylparaben 0.05 Blackcurrant-flavor 10.00 Soluble Red color 0.02 Purified water add 1000 ml

Example 7 Liquid Oral Formulation

Another suitable formulation for 1 liter of a liquid mixture containing2 milligrams of active ingredient in one milliliter of the mixture is asfollows: g Active Ingredient 2 Saccharose 400 Bitter orange peeltincture 20 Sweet orange peel tincture 15 Purified water add 1000 ml

Example 8 Aerosol Formulation

180 g of the aerosol solution contain: g Active Ingredient 10 Oleic acid5 Ethanol 81 Purified Water 9 Tetrafluoroethane 75

15 ml of the solution are filled into aluminum aerosol cans, capped witha dosing valve, purged with 3.0 bar.

Example 9 Trans-Dermal-System formulation

100 g of the solution contain: g Active Ingredient 10.0 Ethanol 57.5Propyleneglycol 7.5 Dimethylsulfoxide 5.0 Hydroxyethylcellulose 0.4Purified water 19.6

1.8 ml of the solution is placed on a fleece covered by an adhesivebacking foil. The system is closed by a protective liner which will beremoved before use.

Example 10 Nanoparticle Formulation

10 g of polybutylcyanoacrylate nanoparticles contain: g ActiveIngredient 1.00 Poloxamer 0.10 Butylcyanoacrylate 8.75 Mannitol 0.10Sodium chloride 0.05

Polybutylcyanoacrylate nanoparticles are prepared by emulsionpolymerization in a water/0.1 N HCl/ethanol mixture as polymerizationmedium. The nanoparticles in the suspension are finally lyophilizedunder vacuum.

Example 11 Suspension Formulation

1.0 g of the suspension contains the following: g Active Ingredient 0.10Hypromellose 0.01 Purified water Ad 1.0 g

Hypromellose is dispersed in water homogeneously with a high speedmixer/blender. After about one hour of hydration time of thehypromellose, the active ingredient is blended homogeneously into thehypromellose solution. The viscosity of the suspension can be adjustedby the amount of hypromellose, resulting in a very stable suspensionwith a very slow tendency of particle sedimentation and particleagglomeration.

Example 12 Solution for Injection

1.0 ml of solution contain: g Active Ingredient 0.05 Mannitol q.s. DMSO0.10 Water for injection Ad 1.0 ml

The active ingredient is dissolved in DMSO by stirring and heating(solution 1). The mannitol is dissolved in WFI (solution 2). Aftercooling down to room temperature solution 1 is mixed with solution 2 bycontinuous stirring. The solution is sterilized by filtration of byautoclaving.

Pharmacology

The active principles of the present invention, and pharmaceuticalcompositions containing them and method of treating therewith, arecharacterized by unique and advantageous properties. The compounds andpharmaceutical compositions thereof exhibit, in standard acceptedreliable test procedures, the following valuable properties andcharacteristics

methods

Binding Assays for the Characterization of mGluR5 Antagonists

[³H]-MPEP (2-methyl-6-(phenylethynyl)pyridine) binding to transmembraneallosteric modulatory sites of mGluR5 receptors in cortical membranes.

Preparation of Rat Cortical Membranes:

Male Sprague-Dawley rats (200-250 g) are decapitated and their brainsare removed rapidly. The cortex is dissected and homogenized in 20volumes of ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. Thehomogenate is centrifuged at 1000×g for 10 minutes. The pellet isdiscarded and the supernatant centrifuged at 20,000×g for 20 minutes.The resulting pellet is re-suspended in 20 volumes of distilled waterand centrifuged for 20 minutes at 8000×g. Then the supernatant and thebuffy coat are centrifuged at 48,000×g for 20 minutes in the presence of50 mM Tris-HCl, pH 8.0. The pellet is then re-suspended and centrifugedtwo to three more times at 48,000×g for 20 minutes in the presence of 50mM Tris-HCl, pH 8.0. All centrifugation steps are carried out at 4° C.After resuspension in 5 volumes of 50 mM Tris-HCl, pH 8.0 the membranesuspension is frozen rapidly at −80° C.

On the day of assay the membranes are thawed and washed four times byresuspension in 50 mM Tris-HCl, pH 8.0 and centrifugation at 48,000×gfor 20 minutes and finally re-suspended in 50 mM Tris-HCl, pH 7.4. Theamount of protein in the final membrane preparation (500-700 μg/ml) isdetermined according to the method of Lowry (Lowry 0. H. et al. 1951. J.Biol. Chem. 193, 256-275).

[³H]-MPEP Assay

Incubations are started by adding [³H]-MPEP (50.2 Ci/mmol, 5 nM, Tocris,GB) to vials with 125-250 μg protein (total volume 0.25 ml) and variousconcentrations of the agents. Alternatively, assays are performed with[³H]-MMPEP (2-(3-methoxyphenylethynyl)-6-methylpyridine hydrochloride)as radioligand. The incubations are continued at room temperature for 60minutes (equilibrium is achieved under the conditions used).Non-specific binding is defined by the addition of unlabeled MPEP (10μM). Incubations are terminated using a Millipore filter system. Thesamples are rinsed twice with 4 ml of ice-cold assay buffer over glassfibre filters (Schleicher & Schuell, Germany) under a constant vacuum.Following separation and rinse, the filters are placed intoscintillation liquid (5 ml Ultima Gold, Perkin Elmer, Germany) andradioactivity retained on the filters is determined with a conventionalliquid scintillation counter (Canberra Packard, Germany).

Characterization:

Specific binding is extremely high i.e. normally >85% and essentiallyindependent of buffer (Tris or HEPES both 50 mM) and pH (6.8-8.9). Thereis a clear saturable protein dependence and the chosen proteinconcentration used for subsequent assays (500-700 μg/ml) is within thelinear portion of this dependence. Cold MPEP displaces hot ligand withan IC₅₀ of 11.2±0.64 nM. The K_(d) of [³H]-MPEP of 13.6 nM is determinedby Scatchard analysis and used according to the Cheng Prussoffrelationship to calculate the affinity of displacers as K_(d) values(IC₅₀ of cold MPEP equates to a K_(i) of 8.2 nM). B_(max) is 0.56 pm/mgprotein.

Functional Assays of mGluR5 Receptors

Cytosolic Calcium Studies with Stably Transfected Cells

Chinese hamster ovary cells (CHO-K1 cells), stably transfected forinducible expression of a human metabotropic glutamate receptor mGluR5,are seeded into black clear bottom 96 well plates at a density of 35.000cells per well. The standard growth medium used (Dulbecco's modifiedEagle Medium, DMEM plus L-proline) contains the appropriate inducerisopropyl-β-D-thiogalactopyranosid (IPTG) to achieve optimal receptorexpression. One day after seeding the growth medium is exchanged forreconstituted Ca-Kit (Molecular Devices, USA) and incubated for onehour. Ca-Kit is reconstituted in an assay buffer containing 20 mM HEPESpH 7.4, glutamic-pyruvate transaminase, pyridoxal phosphate and sodiumpyruvate in Hank's balanced salt solution (HBBS). Agonistic compounds tothe receptor elicit increases in cytosolic calcium which can be measuredas increases in fluorescence signals by use of a fluorescence imagingplate reader (Molecular Devices). To analyze their potency to modulatethe Ca-response test compounds, dissolved in a final DMSO concentrationof 0.5%, are added on-line 5 minutes before the agonist to the receptor(L-quisqualic acid at a concentration giving ˜80% of the maximalsignal).

Astrocyte Culture:

Primary astrocyte cultures are prepared from cortices of newborn rats asdescribed by Booher and Sensenbrenner (1972, Neurobiology 2(3):97-105).Briefly, Sprague-Dawley rat pups (2-4 d old) are decapitated andneocortices are dissected, disintegrated with a nylon filter (pore size80 μm) and carefully triturated. The cell suspension is plated onpoly-D-lysine pre-coated flasks (Costar, Netherlands) and cultivated inDulbecco's Modified Eagle's Medium (DMEM, Invitrogen, Germany)supplemented with 10% foetal calf serum (FCS, Sigma, Germany), 4 mMglutamine and 50 μg/ml gentamycin (both Biochrom, Germany) at 37° C. ina humidified atmosphere of 5% CO₂/95% air for 7 d with exchanging themedium at day 2 and 6.

After 7 days in vitro (DIV), cells are shaken overnight at 250 rpm toremove oligodendrocytes and microglia. The next day, astrocytes arerinsed twice with CMF-PBS (calcium- and magnesium-free phosphatebuffered saline, Biochrom, Germany), trypsinized and subplated onpoly-D-lysine pre-coated 96-well plates (Greiner, Germany) at a densityof 40,000 cells/well. 24 h after establishing the secondary culture theastrocytes are rinsed with PBS⁺⁺ (phosphate buffered saline, Biochrom,Germany) and fed with astrocyte-defined medium (ADM) consisting of DMEMcontaining 1× G5-supplement (Invitrogen, Germany), 0.5 μg/ml heparansulfate, and 1.5 μg/ml fibronectin (both Sigma, Germany) (Miller et al.,(1993) Brain Res. 618(1):175-8). 3 d later the medium is exchanged andthe cells incubated for another 2-3 d, so that at the time ofexperiments astrocytes are 14-15 DIV.

Immunocytochemistry

Immunostaining is performed to confirm the presence of astrocyticmarkers such as the glial fibrillary acidic protein (GFAP) as well as tomonitor the expression of mGluR5 receptors.

Cytosolic Calcium Studies with Astrocytes:

The increase of cytosolic calcium after stimulation with the mGluR5agonist L-quisqualate is measured using a fluorometric imaging platereader (FLIPR) and the Ca-Kit (both Molecular Devices). Prior toaddition of agonist or antagonist the medium is aspirated and cells areloaded for 2 h at RT with 150 μl of loading buffer consisting ofCa-sensitive dye reconstituted in sodium chloride (123 mM), potassiumchloride (5.4 mM), magnesium chloride (0.8 mM), calcium chloride (1.8mM), D-glucose (15 mM), and HEPES (20 mM), pH 7.3. Subsequently, platesare transferred to FLIPR to detect calcium increase with the addition ofL-quisqualate (100 nM) measured as relative fluorescence units (RFU). Ifantagonists are tested, these compounds are pre-incubated for 10 minutesat RT before addition of the respective agonist.

For positive modulators, concentration-response curves for quisqualateare performed in the presence and absence of 10 μM modulator todetermine the extent of potentiation/agonist potency increase.Thereafter, concentration-response curves for the positive modulator areperformed in the presence of a fixed concentration of quisqualateshowing the biggest window for potentiation (normally 10-30 nM).

Data Analysis

The fluorescence signal increase after addition of agonist reflects theincrease of cytosolic calcium. Inconsistencies in the amount of cellsper well are normalized by using the spatial uniformity correction ofthe FLIPR software. The mean of replicated temporal data (n=3-5) iscalculated and used for graphical representation. For the evaluation ofthe pharmacology, the calcium changes in response to differentconcentrations of agonist or antagonist are determined using a maximumminus minimum (MaxMin) calculation.

All responses (RFU-values) are determined as percentage of control(=maximum response). EC₅₀ and IC₅₀ are calculated according the logisticequation using GraFit 5.0 (Erithacus Software, GB) or Prism 4.0(GraphPad Software, USA). The compounds of the present invention have apotency (IC₅₀) within a range of about 0.5 nM to about 100 μM.

Results for representative compounds of the invention are shown inTables A1-A3.

In conclusion, from the foregoing, it is apparent that the presentinvention provides novel and valuable applications and uses of thecompounds of the present invention, which compounds comprise the activeprinciple according to the present invention, as well as novelpharmaceutical compositions thereof and methods of preparation thereofand of treating therewith.

The high order of activity of the active agent of the present inventionand compositions thereof, as evidenced by the tests reported, isindicative of utility based on its valuable activity in human beings aswell as in lower animals. Clinical evaluation in human beings has notbeen completed. It will be clearly understood that the distribution andmarketing of any compound or composition falling within the scope of thepresent invention for use in human beings will of course have to bepredicated upon prior approval by governmental agencies which areresponsible for and authorized to pass judgment on such questions.

The instant compounds of formula (I) represent a novel class of mGluR5modulators. In view of their potency, they will be useful therapeuticsin a wide range of disorders, in particular CNS disorders, which involveexcessive glutamate induced excitation.

These compounds accordingly find application in the treatment of thedisorders of a living animal body, especially a human, as listed earlierin the description.

These compounds also find application in the treatment of indications ina living animal body, especially a human, wherein a particular conditiondoes not necessarily exist but wherein a particular physiologicalparameter may be improved through administration of the instantcompounds, including cognitive enhancement.

Neuroprotection as well as cognitive enhancement can also be achieved bycombining application of these compounds with NMDA receptor antagonistslike Memantine and Neramexane.

The method-of-treating a living animal body with a compound of theinvention, for the inhibition of progression or alleviation of theselected ailment therein, is as previously stated by anynormally-accepted pharmaceutical route, employing the selected dosagewhich is effective in the alleviation of the particular ailment desiredto be alleviated. Use of the compounds of the present invention in themanufacture of a medicament for the treatment of a living animal forinhibition of progression or alleviation of selected ailments orconditions, particularly ailments or conditions susceptible to treatmentwith a Group I mGluR modulator is carried out in the usual mannercomprising the step of admixing an effective amount of a compound of theinvention with a pharmaceutically-acceptable diluent, excipient, orcarrier, and the method-of-treating, pharmaceutical compositions, anduse of a compound of the present invention in the manufacture of amedicament.

Representative pharmaceutical compositions prepared by admixing theactive ingredient with a suitable pharmaceutically-acceptable excipient,diluent, or carrier, include tablets, capsules, solutions for injection,liquid oral formulations, aerosol formulations, TDS formulations, andnanoparticle formulations, thus to produce medicaments for oral,injectable, or dermal use, also in accord with the foregoing. TABLE A1(Cytosolic Calcium studies with stably transfected cells) CompoundChemical Name mGluR5_FLIPR_h_CHONAM_IC50 [μM]

6-bromo-2-[(4-phenyl-3,6- dihydro-1(2H)-pyridinyl)carbonyl]pyrazolo[1,5- a]pyrimidine; Example 1 0.4930

TABLE A2 (Astrocyte culture test) mGluR5_FLIPR_r_rpA Compound ChemicalName IC50 [μM]

6-bromo-2-[(4-phenyl-3,6-dihydro- 1(2H)-pyridinyl)carbonyl]pyrazolo[1,5- a]pyrimidine; Example 1 0.08

TABLE A3 (³H-MPEP Assay) mGluR5_MPEP Compound Chemical Name rCTX_IC50[μM]

6-bromo-2-[(4-phenyl-3,6-dihydro- 1(2H)-pyridinyl)carbonyl]-pyrazolo[1,5-a]pyrimidine; Example 1 0.25

1. A compound selected from those of formula (I)

wherein R¹ represents chloro or bromo; R² and R³ each independentlyrepresent hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl; or R²and R³ both together with the carbon atom of the ring represent acarbonyl group; R⁴ and R⁵ each independently represent hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl; or R⁴ and R⁵ both togetherwith the carbon atom of the ring represent a carbonyl group; R⁶ and R⁷independently represent hydrogen, C₁₋₆-alkyl, C₃₋₇cycloalkyl ortrifluoromethyl; or R⁶ and R⁷ both together with the carbon atom of thering represent a carbonyl group; R² or R³ together with R⁶ and R⁷ mayalso form a bivalent radical selected from the group CH₂—CH₂ and CH₂—O;R⁸ represents a radical R⁹ or a radical R¹⁰, whereby one of the tworadicals R⁸ represents R⁹ and the other radical R⁸ represents R¹⁰; R⁹represents a cyclic group selected from aryl, heteroaryl orheterocyclyl, wherein the ring system may be optionally substituted byone or two substituents, which may be the same or different and selectedindependently from halogen, amino, hydroxyl, nitro, cyano,trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl andC₁₋₆alkoxy; R¹⁰ represents hydrogen or C₁₋₆alkyl; and optical isomers,pharmaceutically acceptable salts, hydrates, solvates, and polymorphsthereof.
 2. The compound of claim 1, wherein R², R³, R⁴, R⁵, R⁶ and R⁷independently represent hydrogen, C₁₋₆-alkyl, C₃₋₇cycloalkyl ortrifluoromethyl; and one of the radicals R⁸ represents hydrogen ormethyl and the other radical R⁸ represents a phenyl, thiophene, pyrrole,tetrazole, furane, pyridine or pyrimidine ring, wherein the ring systemmay be substituted by one substituent selected from halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl and C₁₋₆alkoxy. 3.The compound of claim 1, wherein one of the radicals R⁸ representshydrogen and the other radical R⁸ represents a phenyl, thiophene,pyrrole, tetrazole, furan, pyridine or pyrimidine ring which may beoptionally substituted by one substituent selected from halogen, amino,hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl,hydroxyC₁₋₆alkyl and C₁₋₆alkoxy.
 4. The compound of claim 1, wherein R⁶and R⁷ represent hydrogen.
 5. The compound of claim 1, wherein R², R³,R⁴ and R⁵ independently represent hydrogen, methyl, ethyl ortrifluoromethyl; and R⁶ and R⁷ independently represent hydrogen ormethyl.
 6. The compound of claim 1, wherein R², R³, R⁴, R⁵, R⁶ and R⁷independently represent hydrogen, methyl or ethyl.
 7. The compound ofclaim 1, wherein R² and R³ independently represent hydrogen, methyl orethyl.
 8. The compound of claim 1, wherein R² represents methyl or ethyland R³ represents hydrogen and which has at least one chiral carbonatom.
 9. The compound of claim 1, wherein R² represents hydrogen ormethyl and R³, R⁴, R⁵, R⁶ and R⁷ represent hydrogen.
 10. The compound ofclaim 1, wherein R¹ represents chloro.
 11. The compound of claim 1,wherein R¹ represents bromo.
 12. The compound of claim 1, wherein R²,R³, R⁴, R⁵, R⁶ and R⁷ represent hydrogen.
 13. The compound of claim 1,wherein R², R³, R⁴, R⁵, R⁶ and R⁷ represent hydrogen, and the radical R⁸which is in 3-position of the dihydro-pyridin-ring system representshydrogen.
 14. The compound of claim 1, wherein the radical R⁸ which isin 4-position of the dihydro-pyridin-ring represents a phenyl,thiophene, pyrrole, tetrazole, furan, pyridine or pyrimidine ring,wherein the ring system may be substituted by one substituent selectedfrom halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl,trifluoromethoxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl and C₁₋₆alkoxy.
 15. Thecompound of claim 1, wherein the radical R⁸ which is in 3-position ofthe dihydro-pyridin-ring represents hydrogen, and the radical R⁸ whichis in 4-position of the dihydro-pyridin-ring represents a phenyl,pyridine or pyrimidine ring, wherein the ring system may be substitutedby one substituent selected from halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, C₁₋₆alkyl and C₁₋₆alkoxy.
 16. The compound of claim 1,wherein the radical R⁸ which is in 3-position of thedihydro-pyridin-ring represents hydrogen, and the radical R⁸ which is in4-position of the dihydro-pyridin-ring represents a phenyl ring whichmay be substituted by one substituent selected from halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl and C₁₋₆alkoxy. 17.The compound of claim 1, which is selected from:(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone,6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4′]bipyridinyl-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dihydro-2H-[4,4′]bipyridinyl-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dihydro-2H-[3,4′]bipyridinyl-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5′,6′-dihydro-2′H-[2,3′]bipyridinyl-1′-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5′,6′-dihydro-2′H-[2,3′]bipyridinyl-1′-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-thiophen-2-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1-methyl-1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-5-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2′-methyl-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2′-methyl-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-3,6-dihydro-2H-[4,4′]bipyridinyl-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-thiophen-2-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-furan-2-yl-2-methyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-pyrrol-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methaone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,[4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(2-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(3-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(4-Bromo-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(3-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(2-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(3-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,[4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-2-methyl-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[2-methyl-4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[4-(1H-tetrazol-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-pyrimidin-5-yl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2-methyl-4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone,(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanoneand(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-p-tolyl-3,6-dihydro-2H-pyridin-1-yl)-methanone.18. A method for treating or preventing a condition or diseaseassociated with abnormal glutamate neurotransmission, or a method formodulating mGluR5 receptors to achieve therapeutic benefit, such methodcomprising the step of administering to a living animal, including ahuman, a therapeutically effective amount of a compound of claim
 1. 19.The method of claim 18, wherein the condition associated with abnormalglutamate transmission, or wherein modulation of mGluR5 receptorsresults in therapeutic benefit is selected from: Alzheimer's disease,Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy(BSE), prion related infections, diseases involving mitochondrialdysfunction, diseases involving β-amyloid and/or tauopathy, Down'ssyndrome, hepatic encephalopathy, Huntington's disease, motor neurondiseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellaratrophy, post-operative cognitive deficit (POCD), systemic lupuserythematosus, systemic clerosis, Sjogren's syndrome, Neuronal CeroidLipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson'sdisease, Parkinson's dementia, mild cognitive impairment, cognitivedeficits in various forms of mild cognitive impairment, cognitivedeficits in various forms of dementia, dementia pugilistica, vascularand frontal lobe dementia, cognitive impairment, learning impairment,eye injuries, eye diseases, eye disorders, glaucoma, retinopathy,macular degeneration, head or brain or spinal cord injuries, head orbrain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatalhypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke orbypass operations or transplants, convulsions, epileptic convulsions,epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult,inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner earinsult, sound- or drug-induced tinnitus, L-dopa-induced dykinesias,L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias,dyskinesia in Huntington's disease, drug induced dyskinesias,neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias,dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea,athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, ticdisorder, torticollis spasmodicus, blepharospasm, focal and generalizeddystonia, nystagmus, hereditary cerebellar ataxias, corticobasaldegeneration, tremor, essential tremor, abuse, addiction, nicotineaddiction, nicotine abuse, alcohol addiction, alcohol abuse, opiateaddiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamineaddiction, amphetamine abuse, anxiety disorders, panic disorders,anxiety and panic disorders, social anxiety disorder (SAD), attentiondeficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS),restless leg syndrome (RLS), hyperactivity in children, autism,dementia, dementia in Alzheimer's disease, dementia in Korsakoffsyndrome, Korsakoff syndrome, vascular dementia, dementia related to HIVinfections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementiacomplex, AIDS-related dementia, major depressive disorder, majordepression, depression, depression resulting from Borna virus infection,major depression resulting from Borna virus infection, bipolarmanic-depressive disorder, drug tolerance, drug tolerance to opioids,movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS),migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain,acute pain, inflammatory pain, neuropathic pain, diabetic neuropathicpain (DNP), pain related to rheumatic arthritis, allodynia,hyperalgesia, nociceptive pain, cancer pain, posttraumatic stressdisorder (PTSD), schizophrenia, positive or cognitive or negativesymptoms of schizophrenia, spasticity, Tourette's syndrome, urinaryincontinence, vomiting, pruritic conditions, pruritis, sleep disorders,micturition disorders, neuromuscular disorder in the lower urinarytract, gastroesophageal reflux disease (GERD), gastrointestinaldysfunction, lower esophageal sphincter (LES) disease, functionalgastrointestinal disorders, dyspepsia, regurgitation, respiratory tractinfection, bulimia nervosa, chronic laryngitis, asthma, reflux-relatedasthma, lung disease, eating disorders, obesity, obesity-relateddisorders, obesity abuse, food addiction, binge eating disorders,agoraphobia, generalized anxiety disorder, obsessive-compulsivedisorder, panic disorder, posttraumatic stress disorder, social phobia,phobic disorders, substance-induced anxiety disorder, delusionaldisorder, schizoaffective disorder, schizophreniform disorder,substance-induced psychotic disorder, or delirium; inhibition of tumourcell growth, migration, invasion, adhesion and toxicity in theperipheral tissues, peripheral nervous system and CNS; neoplasia,hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer,squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lungcancer, lung adenocarcinoma, breast cancer, prostate cancer, gastriccancer, liver cancer, colon cancer, colorectal carcinoma,rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma,malignant glioma, astroglioma, neuroglioma, neuroblastoma, glioblastoma,medulloblastoma, cancer of skin cells, melanoma, malignant melanoma,epithelial neoplasm, lymphoma, myeloma, Hodgkin's disease, Burkitt'slymphoma, leukemia, thymoma, and other tumours.
 20. The method of claim18, wherein the condition associated with abnormal glutamatetransmission, or wherein modulation of mGluR5 receptors results intherapeutic benefit is selected from: chronic pain, neuropathic pain,diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathicarthritis, inflammatory pain, L-dopa-induced dyskinesias,dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias inParkinson's disease therapy, dopaminomimetic-induced dyskinesias inParkinson's disease therapy, tardive dyskinesias, Parkinson's disease,anxiety disorders, panic disorders, anxiety and panic disorders, socialanxiety disorder (SAD), generalized anxiety disorder, substance-inducedanxiety disorder, eating disorders, obesity, binge eating disorders,Huntington's chorea, epilepsy, Alzheimer's disease, positive andnegative symptoms of schizophrenia, cognitive impairment, functionalgastrointestinal disorders, gastroesophageal reflux disease (GERD),migraine, irritable bowel syndrome (IBS), or for cognitive enhancementand/or neuroprotection.
 21. The method of claim 18, wherein thecondition associated with abnormal glutamate transmission, or whereinmodulation of mGluR5 receptors results in therapeutic benefit isselected from: chronic pain, neuropathic pain, diabetic neuropathic pain(DNP), cancer pain, pain related to rheumathic arthritis, inflammatorypain, L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias,L-dopa-induced dyskinesias in Parkinson's disease therapy,dopaminomimetic-induced dyskinesias in Parkinson's disease therapy,tardive dyskinesias, Parkinson's disease, anxiety disorders, panicdisorders, anxiety and panic disorders, social anxiety disorder (SAD),generalized anxiety disorder, substance-induced anxiety disorder, eatingdisorders, obesity, binge eating disorders, migraine, irritable bowelsyndrome (IBS), functional gastrointestinal disorders, gastroesophagealreflux disease (GERD), Huntington's chorea and epilepsy.
 22. The methodof claim 18, wherein the condition associated with abnormal glutamatetransmission, or wherein modulation of mGluR5 receptors results intherapeutic benefit is selected from: Alzheimer's disease, positiveand/or negative symptoms of schizophrenia, cognitive impairment, orcognitive enhancement and neuroprotection.
 23. The method of claim 18,wherein the condition associated with abnormal glutamate transmission,or wherein modulation of mGluR5 receptors results in therapeuticbenefit, is a binge eating disorder.
 24. A pharmaceutical compositioncomprising as active ingredient at least one compound of claim 1together with one or more pharmaceutically acceptable excipients.
 25. Apharmaceutical composition comprising a combination of at least onecompound of claim 1 and at least one NMDA receptor antagonist, togetherwith one or more pharmaceutically acceptable excipients.
 26. A processfor the synthesis of a compound selected from those of formula (I)

wherein R¹ represents chloro or bromo; R² and R³ each independentlyrepresent hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl; or R²and R³ both together with the carbon atom of the ring represent acarbonyl group; R⁴ and R⁵ each independently represent hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl; or R⁴ and R⁵ both togetherwith the carbon atom of the ring represent a carbonyl group; R⁶ and R⁷independently represent hydrogen, C₁₋₆-alkyl, C₃₋₇cycloalkyl ortrifluoromethyl; or R⁶ and R⁷ both together with the carbon atom of thering represent a carbonyl group; R² or R³ together with R⁶ and R⁷ mayalso form a bivalent radical selected from the group CH₂—CH₂ and CH₂—O;R⁸ represents a radical R⁹ or a radical R¹⁰, whereby one of the tworadicals R⁸ represents R⁹ and the other radical R⁸ represents R¹⁰; R⁹represents an aryl, heteroaryl or heterocycle, wherein the ring systemmay be optionally substituted by one or two substituents, which may bethe same or different and selected independently from halogen, amino,hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl,hydroxyC₁₋₆alkyl and C₁₋₆alkoxy; R¹⁰ represents hydrogen or C₁₋₆alkyl;and optical isomers, pharmaceutically acceptable salts, hydrates,solvates, and polymorphs thereof, wherein a compound of formula (II)

is suspended in a mixture of ethanol and water and treated withhydrochloric acid, followed by reaction with H₂NNHCOOCH₃ to yield acompound of Formula (III)

which is reacted with a compound of Formula (IV)

to yield a compound of Formula (V)

which is hydrolyzed under acidic conditions to yield a compound ofFormula (VI)

which is treated with an amine of Formula (VII)

in the presence of a condensing agent, to yield a compound of Formula(I), which is converted, if desired, to a pharmaceutically acceptablesalt, hydrate, solvate, or polymorph.
 27. A compound selected from thoseof formula (VII)

wherein R² and R³ each independently represent hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl or trifluoromethyl; or R² and R³ both together with thecarbon atom of the ring represent a carbonyl group; R⁴ and R⁵ eachindependently represent hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl ortrifluoromethyl; or R⁴ and R⁵ both together with the carbon atom of thering represent a carbonyl group; R⁶ and R⁷ independently representhydrogen, C₁₋₆-alkyl, C₃₋₇cycloalkyl or trifluoromethyl; or R⁶ and R⁷both together with the carbon atom of the ring represent a carbonylgroup; R² or R³ together with R⁶ and R⁷ may also form a bivalent radicalselected from the group CH₂—CH₂ and CH₂—O; R⁸ represents a radical R⁹ ora radical R¹⁰, whereby one of the two radicals R⁸ represents R⁹ and theother radical R⁸ represents R¹⁰; R⁹ represents a cyclic group selectedfrom aryl, heteroaryl or heterocyclyl, wherein the ring system may beoptionally substituted by one or two substituents, which may be the sameor different and selected independently from halogen, amino, hydroxyl,nitro, cyano, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl,hydroxyC₁₋₆alkyl and C₁₋₆alkoxy; R¹⁰ represents hydrogen or C₁₋₆alkyl.28. A process for the synthesis of a compound selected from those offormula (I)

wherein R¹ represents chloro or bromo; R² and R³ each independentlyrepresent hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl; or R²and R³ both together with the carbon atom of the ring represent acarbonyl group; R⁴ and R⁵ each independently represent hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl or trifluoromethyl; or R⁴ and R⁵ both togetherwith the carbon atom of the ring represent a carbonyl group; R⁶ and R⁷independently represent hydrogen, C₁₋₆-alkyl, C₃₋₇cycloalkyl ortrifluoromethyl; or R⁶ and R⁷ both together with the carbon atom of thering represent a carbonyl group; R² or R³ together with R⁶ and R⁷ mayalso form a bivalent radical selected from the group CH₂—CH₂ and CH₂—O;R⁸ represents a radical R⁹ or a radical R¹⁰, whereby one of the tworadicals R⁸ represents R⁹ and the other radical R⁸ represents R¹⁰; R⁹represents a cyclic group selected from aryl, heteroaryl orheterocyclyl, wherein the ring system may be optionally substituted byone or two substituents, which may be the same or different and selectedindependently from halogen, amino, hydroxyl, nitro, cyano,trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl andC₁₋₆alkoxy; R¹⁰ represents hydrogen or C₁₋₆alkyl; and optical isomers,pharmaceutically acceptable salts, hydrates, solvates, and polymorphsthereof, wherein a compound of Formula (VIII)

is dissolved in an alcoholic solvent and treated with thionyl chlorideto yield a compound of Formula IX

wherein PG represents C₁₋₆alkyl, which is reduced under standardconditions to yield a compound of Formula X

which is reacted with a compound of Formula (IV)

to yield a compound of Formula (XI)

which is hydrolyzed under acidic conditions to yield a compound ofFormula (VI)

which is treated with an amine of Formula (VII)

in the presence of a condensing agent, to yield a compound of Formula(I), which is converted, if desired, to a pharmaceutically acceptablesalt, hydrate, solvate, or polymorph.